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Abstract

  1. Top of page
  2. Abstract
  3. Inhaled insulin
  4. Inhaled insulin – Exubera
  5. Inhaled insulin – air insulin
  6. Inhaled insulin – technosphere
  7. Inhaled insulin – others
  8. Oral insulin
  9. Nasal insulin
  10. Buccal insulin
  11. Insulin pens
  12. Miscellaneous
  13. References

The predominant number of papers published from the middle of 2009 to the middle of 2010 about alternative routes of insulin administration (ARIA) were still about inhaled insulin. Long-term experience with Exubera was the topic of a number of publications that are also of relevance for inhaled insulin in general. The clinical trials performed with AIR insulin by Eli Lilly were published in a supplement issue of one diabetes technology journal and most of these will be presented. A number of other publications (also one in a high ranked journal) about their inhaled insulin were from another company: MannKind. The driving force behind Technosphere insulin (TI) – which is the only one still in clinical development – is Al Mann; he has put a lot of his personal fortune in this development. We will know the opinion of the regulatory authorities about TI in the near future; however, I am personally relatively confident that the Food and Drug Administration will provide TI with market approval. The more critical question for me is: will diabetologists and patients jump on this product once it becomes commercially available? Will it become a commercial success? In view of many negative feelings in the scientific community about inhaled insulin, it might be of help that MannKind publish their studies with TI systematically. Acknowledging being a believer in this route of insulin administration myself, one has to state that Exubera and AIR insulin had not offered profound advantages in terms of pharmacokinetic (PK) and pharmacodynamic (PD) properties in comparison with subcutaneously (SC) applied regular human insulin (RHI) and rapid-acting insulin analogues. The time–action profiles of these inhaled insulins were more or less comparable with that of rapid-acting insulin analogues. This is clearly different with TI which exhibits a strong metabolic effect shortly after application and a rapid decline in the metabolic effect thereafter; probably the duration of action is even too short (see postprandial glycaemic excursions with test meals in the publication by Rosenstock et al. in The Lancet (1)). In the end a number of aspects are of relevance for the success of a given product; one key aspect is clearly the price. However, for patients also practical aspects (handling, need for regular pulmonary function test etc.) are of importance. We shall have to see how creatively MannKind will handle all such questions. Until now Al Mann and his colleagues were able to manage a number of challenges during the clinical development process successfully, so one can have hopes for the market success of TI. However, it is clear that at the same time, if TI fails like Exubera did before, this will be the end for pulmonary insulin in general. Not too many original publications presenting data from clinical trials were published in the last year when it comes to oral insulin (OI), nasal insulin or transdermal insulin developments; simply none with transdermal insulin. Also at the last international congresses not many studies about ARIA were presented. At least in part this might be still a reflection of the shockwaves that the failure of Exubera has sent out to pharmaceutical companies and venture capitalists; they are quite reluctant to invest in any of these developments. However, a considerable number of reviews (in some cases more than original papers!) were published about ARIA. These reviews are listed for completeness, but in most cases are not further commented. OI is still the area of research most companies are active in; however, in some cases it is not clear how active they really are (e.g. Diabetology). Nevertheless, at least some companies are quite active and progressed in their clinical development programme close to market approval, e.g. the large Indian company Biocon is in late phase 3 with IN-105 and the small Israel-based company Oramed is in phase 2b. It appears that other interesting OI developments (e.g. Diasome) were not very active in the last year; at least they have not published new study results. It is clear that for companies that produce insulin themselves (e.g. Biocon) the costs of the good are not of such relevance as for companies that have to buy it commercially. For the latter ones a low bioavailability/biopotency compared with SC insulin administration can be a real hurdle when it comes to the price of their product. Despite some publications about nasal insulin, the overall activity with this route of insulin administration appears to be low; the same holds true for transdermal insulin. Insulin pens have gained more scientific interest in recent years, which is also reflected by an increase in publications, starting from practically nil 10 years ago to a solid number of five to 10 papers per year nowadays. Besides ARIA there are also attempts to increase the speed of insulin absorption after injection into the skin by applying it not into the SC tissue but intradermally or by heating up the skin above the SC insulin depot. Reading a number of papers that were not included in this chapter because they do not present any clinical data but are novel developments tested only in animal experiments so far, the clear message is that there is definitely not a lack of creativity/imagination amongst scientists; each year a plethora of new ideas for insulin application show up. Unfortunately not too many make it towards a full clinical development. As long as there is not a single successful product on the market that is based on a given ARIA approach, this area of research will not mature. For many patients, avoiding the need for SC injections is attractive; however, as long as no clear ‘advantage’ can be demonstrated, reimbursement will be difficult to achieve. Living in the time of evidence-based medicine it is clear that ‘relevant’ clinical advantages must be proven. The question is what is relevant. Is it just an improvement in metabolic control (= decrease in HbA1c)? Can this also mean that more patients are willing to start insulin therapy earlier than with conventional SC insulin therapy? With TI we have a product that has improved pharmacological properties (also in comparison to Exubera) for coverage of prandial insulin requirements. Subsequently, in the clinical trials performed, postprandial glycaemic excursions were lower than with SC injection of RHI or rapid-acting insulin analogues. This only in part (if at all) results in an improved metabolic control in general (= lower HbA1c) (see below). The outlook for 2011 is that there are chances that we shall have an inhaled insulin product on the market. Probably also the first OI will be submitted to the regulatory authorities for market approval or will even be available in less regulated markets. In order to select all relevant publications about new ways of insulin delivery I performed a PUBMED search and also checked the table of contents of a number of journals that publish heavily in this area of research as well references in the publications I found for additional references. Selection of the manuscripts from all publications was predominately based on the fact whether they presented data from clinical studies or not. The selected studies were critically reviewed for novelty and appropriate study design etc. In some cases also reviews about a given topic were selected if they provide relevant novel insights.


Inhaled insulin

  1. Top of page
  2. Abstract
  3. Inhaled insulin
  4. Inhaled insulin – Exubera
  5. Inhaled insulin – air insulin
  6. Inhaled insulin – technosphere
  7. Inhaled insulin – others
  8. Oral insulin
  9. Nasal insulin
  10. Buccal insulin
  11. Insulin pens
  12. Miscellaneous
  13. References

When Pfizer stopped Exubera, a number of clinical trials were still ongoing, especially some long-term studies. It is not clear to me how many of the data that Pfizer had collected in such studies in total were published; however, at least some publications came out in the last year. Also a considerable number of papers about AIR insulin were published in a supplement issue of a journal that summarises the data obtained during the clinical development of this inhaled insulin before the development was stopped after the market withdrawal of Exubera. Unfortunately a number of these clinical studies were stopped before they reached the targeted study duration. This in turn limits the meaning of most of them. However, it should be highlighted very positively that Eli Lilly was willing to invest a certain amount of time and money into these publications despite the fact that AIR insulin will never become a product. From a scientific point of view this is highly appreciated; many companies fail to do this once a development is stopped and all the knowledge accumulated in the company in this respect gets lost.

Inhaled insulin – Exubera

  1. Top of page
  2. Abstract
  3. Inhaled insulin
  4. Inhaled insulin – Exubera
  5. Inhaled insulin – air insulin
  6. Inhaled insulin – technosphere
  7. Inhaled insulin – others
  8. Oral insulin
  9. Nasal insulin
  10. Buccal insulin
  11. Insulin pens
  12. Miscellaneous
  13. References

Glycaemic exposure is affected favourably by inhaled human insulin (Exubera) as compared with subcutaneous insulin glargine (Lantus) in patients with type 2 diabetes

M. Hompesch,1A. Kollmeier,1K. Rave,2L. Heinemann,2M. Mitnick,3S. Davies,3T. Strack3

1Profil Institute for Clinical Research Inc., Chula Vista, CA, USA,2Profil Institut für Stoffwechselforschung, Neuss, Germany, and3Pfizer Inc., New York, NY, USA

Diabetes Technol Ther 2009; 11: 307–13

Background: The aim of this study was to evaluate the differences between two regimens on glycaemia: adding either inhaled insulin (Exubera, EXU) or SC insulin glargine (GLA) to the treatment regimens of patients with poorly controlled type 2 diabetes treated with oral antidiabetic drugs (OADs).

Methods: In this crossover randomised study, 40 patients were treated with either EXU three times daily prior to meals or SC GLA once daily for a period of eight treatment days. Glucose concentrations were checked using a continuous glucose monitoring system for the final 72 h.

Results: Total insulin dosage on the last treatment day was 40 ± 18 U/day EXU vs. 16 ± 5 U/day GLA. Over the 72-h continuous glucose monitoring period serum insulin levels were higher with EXU than with GLA (1091 ± 589 vs. 737 ± 386 pmol/ml/h). The glucose exposure over this period was lower with EXU than with GLA (380 ± 45 vs. 426 ± 89 mmol/l/h). The overall hypoglycaemic event rate was 8.7 events per subject-month in patients using EXU and 2.4 for those using GLA.

Conclusions: Using a higher daily insulin dose in prandial insulin therapy with EXU reduces total daily glucose exposure more effectively, mainly postprandial glycaemia, than a long-acting insulin analogue.

  • Comment: The basic idea of this study was to investigate whether prandial insulin therapy with an inhaled insulin is accompanied by better metabolic control than treatment with a once daily SC injection of a long-acting insulin analogue in patients with type 2 diabetes who were poorly controlled with OADs alone. The improvement that could be observed with EXU depends, at least in part, on an insulin dose that was more than twice that with insulin glargine and an increase in hypoglycaemic events with inhaled insulin. Nevertheless, this study shows that combination of inhaled insulin with OADs is an attractive alternative to adding a long-acting insulin analogue to OADs in such patients. We shall have to see if an inhaled insulin with more favourable PK/PD properties (= TI; see below) is better than Exubera in such a head-to-head comparison with respect to long-term outcome measures. This has to be studied in appropriately designed clinical studies.

Glycaemic control with preprandial versus basal insulin in patients with type 2 diabetes mellitus poorly controlled by oral antidiabetes agents

T. Heise,1C. Mathieu,2J. Hey-Hadavi,3T. Strack,3D. Lawrence3

1Profil Institut für Stoffwechselforschung, Neuss, Germany,2University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium, and3Global Medical Research and Development, Pfizer Inc., New York, NY, USA

Diabetes Technol Ther 2010; 12: 135–41

Background: The aim of this study was to compare metabolic control with either once daily basal insulin (BI) (insulin glargine) or preprandial insulin EXU in patients with poorly controlled type 2 diabetes mellitus (T2DM) treated with at least two OADs.

Methods: This was a 26-week, open-label, parallel group, randomised study where patients (n = 257) with mean HbA1c of 8.6% on OAD treatment for 3 months were also treated with either BI (n = 122) or EXU (n = 135). Based on self-monitored blood glucose levels, BI dose was titrated in the morning or before bedtime, whereas EXU dose was adjusted before each major meal.

Results: After 26 weeks, more patients achieved HbA1c < 6.5% (28% vs. 19%) and < 7.0% (63% vs. 55%) with EXU than with BI. EXU had lower post-meal glucose increments, higher pre-breakfast glucose, more weight gain (1.1 kg), more frequent mild or moderate hypoglycaemic events, and less frequent nocturnal hypoglycaemic events compared with BI.

Conclusions: EXU improved postprandial glucose and HbA1c levels significantly more than BI. More patients achieved metabolic control targets with EXU, at the expense of more hypoglycaemia and body weight gain.

  • Comment: This study evaluated the effect of prandial inhaled insulin therapy in the group of patients with type 2 diabetes not well controlled on OADs in whom insulin therapy is going to be started. The question addressed is which type of insulin therapy, is better under this condition: basal or prandial insulin. This relatively large and well-performed study shows with both types of insulin therapy an impressive improvement in metabolic control (decline in HbA1c by 1.2% from a baseline of 8.5%). A greater decline in fasting blood glucose was observed with the basal insulin in this study. In many other studies the inhaled insulin has induced also a larger decline in fasting blood glucose; however, the comparator in such cases was not basal insulin. It is a pity that enrolment in this study was terminated due to the market withdrawal of EXU.

Safety and efficacy of inhaled human insulin (Exubera) during discontinuation and re-administration of therapy in adults with type 2 diabetes: a 3-year randomised controlled trial

J. Rosenstock,1W. T. Cefalu,2P. A. Hollander,3S. S. Klioze,4J. Reis,4W. T. Duggan4

1Dallas Diabetes and Endocrine Center, Dallas, TX, USA,2Pennington Biomedical Research Center, Baton Rouge, LA, USA,3Baylor University Medical Center, Dallas, TX, USA, and4Pfizer Global Research and Development, New London, CT, USA

Diabetes Technol Ther 2009; 11: 697–705

Background: The aim of the study was to assess one of the key questions with inhaled insulin: what is the safety of this route of insulin administration over longer periods of time in adult T2DM patients?

Methods: In all 316 patients were randomised to receive EXU and 311 to receive SC insulin for a 2-year ‘comparative phase’, followed by 6 months of SC insulin ‘washout phase’ and 6 months when the original therapy was given –‘re-administration’. Lung function tests of a high standard were performed throughout all phases.

Results: During the comparative phase, small non-progressive treatment group differences were observed early for parameters such as forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO). These differences resolved during washout and recurred to the same small size during re-administration. There were similar metabolic control and hypoglycaemic event rates in both groups. Insulin antibody (InsAb) levels reached a plateau at 9 months in the EXU group, declined to near baseline levels during washout, and increased during re-administration to levels of the comparative phase.

Conclusions: Lung function changes observed during discontinuation and re-administration of EXU therapy were consistent with a reversible, non-progressive and non-structural pathological effect on lung function in adults with T2DM. Re-administration of inhaled insulin was not associated with an augmented InsAb response.

  • Comment: Assuming that it is not of relevance which type of inhaled insulin is used for treatment of patients with diabetes, this is an important and large study investigating precisely measured changes in lung function over a relatively long period of time. Also the study design (investigating inhaled insulin discontinuation and re-administration) allows the effects of inhaled insulin/Exubera on InsAb formation etc. to be studied also. The observed changes in lung function were small with inhaled insulin; however, the differences between the treatment groups resolved within 4 weeks when EXU was stopped. With re-administration of EXU the changes in lung function showed up again. Of interest is the underlying physiological decline in lung function over time in patients of this age by 1–2% per year. The changes in antibody titres observed over time do not hint towards any significant impact change on insulin therapy etc. However, this long-term study also shows that at least with EXU no difference in metabolic control could be achieved over time compared to SC insulin therapy. Also the differences in body weight were small. The previously observed phenomenon of lower fasting blood glucose levels with inhaled insulin, which is a prandial insulin, was observed again.

Titration of inhaled human insulin (Exubera) in a treat-to-target regimen for patients with type 2 diabetes

P. A. Hollander,1W. T. Cefalu,2M. Mitnick,3D. Lawrence,3J. Rosenstock4

1Baylor University Medical Center, Dallas, TX, USA,2Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA,3Pfizer Inc., New York, NY, USA, and4Dallas Diabetes and Endocrine Center, Dallas, TX, USA

Diabetes Technol Ther 2010; 12: 185–91

Background: The aim of this study was to assess the feasibility of safely achieving target metabolic control (HbA1c ≤ 7%) by intensifying structured insulin titration regimens using EXU in patients with uncontrolled type 2 diabetes treated with OADs.

Methods: In total 107 patients with type 2 diabetes with a mean baseline HbA1c of 8.6% taking two or more OADs participated in a randomised, open-label, parallel, 24-week multicentre trial. They were randomised to adjust EXU before meals following either weekly office visits or more intense twice-weekly telephone/office consultations, using a simple structured titration algorithm seeking to attain specific pre-meal glucose levels. Primary end-point was the percentage of patients reaching HbA1c ≤ 7%, and secondary end-points were change in HbA1c, daily blood glucose profile and rate of hypoglycaemic events.

Results: Metabolic control improved whether EXU was titrated once a week (6.8%) or twice weekly (6.8%), and two-thirds of patients in both groups attained HbA1c ≤ 7% (69% and 67%, respectively). Relative to baseline, blood glucose profiles were reduced at all time points, and postprandial excursion during meal tolerance improved to a similar extent in both groups. The rate of hypoglycaemic events was higher in the twice-weekly than in the once-weekly EXU titration.

Conclusions: Inhaled insulin added to OADs safely allows good metabolic control to be achieved in many patients with type 2 diabetes inadequately controlled if a once- or twice-weekly structured titration regimen is used.

  • Comment: In this large US-based study the frequency of dose titration was studied. It is not surprising that no differences in the improvement of metabolic control etc. were observed. Clearly it would have been very interesting to add an SC prandial insulin control arm to this study (probably also a control arm in which no insulin was added) to see how much of the observed improvement was due to the study effect per se or would have also been achieved with another way of insulin administration. However, this can also be deut of an insufficient uptitration of the inhaled insulin dose.

Inhaled insulin – air insulin

  1. Top of page
  2. Abstract
  3. Inhaled insulin
  4. Inhaled insulin – Exubera
  5. Inhaled insulin – air insulin
  6. Inhaled insulin – technosphere
  7. Inhaled insulin – others
  8. Oral insulin
  9. Nasal insulin
  10. Buccal insulin
  11. Insulin pens
  12. Miscellaneous
  13. References

AIR insulin capsules of different dose strengths may be combined to yield equivalent pharmacokinetics and glucodynamics

A. de la Peña1, M. Seger,1K. Rave,2L. Heinemann,2B. Silverman,3D. B. Muchmore4

1Eli Lilly and Company, Indianapolis, IN, USA,2Profil Institut fuer Stoffwechselforschung GmbH, Neuss, Germany,3Alkermes Inc., Cambridge, MA, USA, and4Halozyme Therapeutics Inc., San Diego, CA, USA

Diabetes Technol Ther 2009; 11 (Suppl 2): S75–S80

Background: In this study the PK and PD properties of AIR insulin were assessed by combining capsules of different strengths in healthy subjects.

Methods: Fifty-nine healthy, non-smoking, male or female subjects with normal pulmonary function participated in an open-label, randomised, crossover glucose clamp study. On the five study days one 6 unit-equivalent (U-eq) capsule containing 2.6 mg of insulin, three 2 U-eq (0.9 mg) capsules (2.7 mg total), one 10 U-eq (3.9 mg) capsule, one 6 U-eq capsule plus two 2 U-eq capsules (4.4 mg total), or two 10 U-eq capsules (7.8 mg total) were applied.

Results: The PK and PD responses to administration of a 6 U-eq capsule were equivalent to three 2 U-eq capsules; 90% confidence interval (CI) was contained within the interval (0.8, 1.25). Similarly, PK/PD responses after administration of a 10 U-eq capsule were comparable to the 6 U-eq plus two 2 U-eq capsule combination. AIR insulin exhibited PK dose proportionality and dose-dependent increases in PD responses over the 2.6–7.8 mg dose range.

Conclusions: After single-dose administration in healthy subjects, AIR insulin showed dose strength interchangeability and dose proportionality.

  • Comment: With Exubera there were interesting differences in the metabolic action induced by applying 3 mg vs. three times 1 mg inhaled insulin, which means that Exubera was not dose proportional and lacked dose strength equivalence. As this study nicely shows, AIR insulin showed a good dose–response relationship and capsules of different strength could be combined. However, the study also shows that the PD properties of AIR insulin were not optimal with respect to coverage of prandial insulin requirements. The onset of insulin action was relatively slow and the duration of action was long with this inhaled insulin. This is something to bear in mind when interpreting the results of the clinical trials presented next.

Efficacy and safety of AIR inhaled insulin compared to insulin lispro in patients with type 1 diabetes mellitus in a 6-month, randomised, non-inferiority trial

A. L. Comulada,1E. Renard,2M. Nakano,3N. Rais,4X. Mao,5D. M. Webb,5Z. Milicevic6

1Instituto de Endocrinologıá, Diabetes and Metabolismo, Toa Baja, Puerto Rico,2Endocrinology Department, Centre Hospitalier Universitaire and University of Montpellier, Montpellier, France,3Eli Lilly Japan K.K., Kobe, Japan,4Chowpatty Medical Center, Mumbai, India,5Eli Lilly and Co., Indianapolis, IN, USA, and6Eli Lilly Regional, Vienna, Austria

Diabetes Technol Ther 2009; 11 (Suppl 2): S17–25

Background: The aim of this study was to compare AIR inhaled insulin vs. SC injection of a rapid-acting insulin analogue in patients with type 1 diabetes with respect to efficacy and safety.

Methods: In all 500 patients with type 1 diabetes were included in this multicentre, 6-month, parallel group, non-inferiority trial. They were randomised to morning doses of basal insulin glargine plus either preprandial SC injections of insulin lispro or inhalation of AIR insulin. The hypothesis was that AIR insulin is non-inferior (upper bound of the 95% CI ≤ 0.4%) to insulin lispro for change-from-baseline HbA1c.

Results: Baseline HbA1c was 7.95% ± 0.08% for both groups. At end-point, HbA1c was lower with SC insulin lispro than with inhaled AIR insulin by 0.3% (p < 0.001). Non-inferiority of inhaled insulin to SC prandial insulin was not demonstrated, but similar percentages of patients in each group achieved HbA1c < 7.0%. Overall daily blood glucose was similar between groups at baseline and end-point. Two-hour postprandial blood glucose change from baseline was higher (p < 0.001) with AIR insulin than with insulin lispro (20.8 ± 4.3 mg/dl vs. 3.3 ± 4.1 mg/dl at 3 months and 15.9 ± 3.1 mg/dl vs.1.7 ± 2.9 mg/dl at end-point). Overall hypoglycaemia was comparable between treatment groups. Lung function of the patients in the AIR group showed a greater decrease in DCCO at end-point (p = 0.020) and greater incidence of cough (p = 0.024) and dyspnoea (p = 0.030). Body weight decreased with inhaled insulin and increased with SC prandial insulin.

Conclusions: SC injection of a rapid-acting insulin analogue provided better metabolic control than inhaled insulin, but this may not be of clinical relevance.

  • Comment: This head-to-head comparison between the SC applied insulin lispro and AIR inhaled insulin confirm what was stated above – the PD properties of the inhaled insulin appear to be not as good as those of SC applied rapid-acting insulin analogues to cover prandial insulin requirements, i.e. the postprandial glycaemic excursions were higher with the inhaled insulin studied. Other inhaled insulins (i.e. TI) most probably have different PD properties from AIR insulin (no direct head-to-head comparison of different inhaled insulin has ever been performed!), which supports better postprandial glycaemic control being achieved with TI (see below).

Two-year efficacy and safety of AIR inhaled insulin in patients with type 1 diabetes: an open-label randomised controlled trial

S. K. Garg,1C. Mathieu,2N. Rais,3H. Gao,4J. A. Tobian,4J. R. Gates,5J. A. Ferguson,4D. M. Webb,4P. Y. Berclaz4

1Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, School of Medicine, Aurora, CO, USA,2University Hospital Gasthuisberg of the Catholic University of Leuven, Leuven, Belgium,3Chowpatty Medical Centre, Mumbai, India,4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA, and5MedScriptus, Bioscience Research Section, Ooltewah, TN, USA

Diabetes Technol Ther 2009; 11 (Suppl 2): S5–16

Background: Intensive insulin therapy enables patients with type 1 diabetes to achieve optimal metabolic control. AIR inhaled insulin appears to be an efficacious and safe alternative to SC prandial insulin.

Methods: In all 385 patients with type 1 diabetes were recruited for this phase 3, 2-year, randomised, open-label, active comparator, parallel group study. They were randomly assigned to receive preprandial AIR insulin or SC insulin (RHI or insulin lispro). Both groups of patients received SC insulin glargine once daily. Efficacy measures included change in HbA1c from baseline to end-point, eight-point self-monitored blood glucose profiles, and insulin dosage. Safety was also evaluated.

Results: In both treatment groups, only 20% of subjects reached a good metabolic control indicated by an HbA1c < 7.0%. A significant difference of 0.44% in HbA1c was seen with SC insulin, but with no difference between the groups in insulin doses or hypoglycaemic events at end-point. Patients in both groups experienced progressive decreases in lung function, but larger (reversible) decrements in DLCO were associated with inhaled insulin. Greater weight gain was seen with SC insulin.

Conclusions: Although the AIR inhaled insulin programme was terminated by the sponsor prior to availability of phase 3 data (for reasons unrelated to safety or efficacy), this trial provides evidence that AIR insulin was less efficacious in improving metabolic control. Inhaled insulin was also associated with a greater decrease in DLCO and increased incidence of cough.

  • Comment: This 24-month comparator trial was the longest controlled study in patients with type 1 diabetes performed with AIR insulin. The outcome was negative; the metabolic control achieved with SC RHI was better than with this inhaled insulin. The study confirms the statements made before that the postprandial metabolic control achieved with AIR insulin was not as good as with SC RHI or insulin lispro. The study provides a lot of interesting data in addition, about lung function using high-quality, centrally read Pulmonary Function Tests, insulin antibodies etc.

Initiation of prandial insulin therapy with AIR inhaled insulin or insulin lispro in patients with type 2 diabetes: a randomised non-inferiority trial

J. L. Gross,1M. Nakano,2G. Colon-Vega,3R. Ortiz-Carasquillo,4J. A. Ferguson,5S. Althouse,5J. A. Tobian,5P. Y. Berclaz,5Z. Milicevic6

1Centro de Pesquisas em Diabetes, Porto Alegre, Brazil,2Eli Lilly and Company, Kobe, Japan,3American Telemedicine Center, San Juan, Puerto Rico,4Manati Medical Center, Manati, Puerto Rico,5Eli Lilly and Company, Indianapolis, IN, USA, and6Eli Lilly and Company, Vienna, Austria

Diabetes Technol Ther 2009; 11 (Suppl 2): S27–34

Background: Many patients with type 2 diabetes delay the start of insulin therapy because of concerns about SC injections. The aim of this study was to compare the effects of AIR inhaled insulin with those of SC insulin on metabolic control and safety.

Methods: This open-label, randomised study in patients with diabetes inadequately controlled by OADs was planned for 24 months. Following a 2-week baseline period, patients continued OADs and were randomised to AIR insulin (= 208) or insulin lispro (= 203) before meals. The primary end-point was change in HbA1c from baseline to 6 months. Non-inferiority was established if the upper limit of the 95% CI of the difference in HbA1c change was ≤ 0.4%.

Results: The number of patients for the 12- and 24-month analyses got smaller by an early termination of the study, but not for the primary 6-month end-point analyses. AIR insulin and SC insulin groups had comparable baseline HbA1c values. Also changes in HbA1c from baseline to 6 months were similar and so were final HbA1c values for both AIR insulin and SC insulin. At 6 months, no differences were observed in eight-point blood glucose profiles, overall and nocturnal hypoglycaemia and weight gain. Greater decreases in pulmonary function were observed in the AIR insulin group at 12 months. Cough was the most frequently reported adverse event.

Conclusions: Insulin treatment with AIR insulin resulted in similar improvement in metabolic control compared with insulin lispro. More frequent cough and greater decrease in lung function were observed with AIR insulin.

  • Comment: It is an interesting idea to start insulin therapy in patients with type 2 diabetes with inhaled insulin instead of SC insulin. One would assume that this is of help as many patients (and their treating physician) are reluctant to start insulin therapy because of the fear of injection pain (at least this is the reason stated). This study showed that AIR insulin was as effective as SC insulin for the initiation of insulin therapy without basal insulin coverage in this group of patients. Also in terms of safety no significant difference between inhaled and SC insulin in terms of adverse events was observed, although the effect on lung function after a longer term of treatment clearly would be of interest.

Comparison of prandial AIR inhaled insulin alone to intensified insulin glargine alone and to AIR insulin plus intensified insulin glargine in patients with type 2 diabetes previously treated with once daily insulin glargine

J. Rosenstock,1F. G. Eliaschewitz,2C. R. Heilmann,3D. B. Muchmore,4R. P. Hayes,3R. M. Belin3

1Dallas Diabetes and Endocrine Center, Dallas, TX, USA,2Hospital Albert Einstein, São Paulo, Brazil,3Eli Lilly and Company, Indianapolis, IN, USA, and4Halozyme, San Diego, CA, USA

Diabetes Technol Ther 2009; 11 (Suppl 2): S63–73

Background: Many patients with type 2 diabetes start their insulin therapy with SC injection of a long-acting insulin analogue once per day. With progression of the disease many of them intensify their insulin therapy to improve metabolic control. The aim of this study was to compare three different intensification approaches: switching from insulin glargine to preprandial AIR inhaled insulin (IN), intensifying glargine (IG), or adding AIR insulin plus intensifying glargine (AIR+IG).

Methods: Patients (n = 560) with HbA1c of 7.5%–10.5%, on one or more oral hypoglycaemia drugs (OADs) and on once daily IG for ≥ 4 months were randomly distributed to one of the three treatments lasting 52 weeks. Primary end-point was the between-group differences in metabolic control as changes from baseline to 24 weeks using last-observation-carried-forward (LOCF) in the intent-to-treat population.

Results: After 24 weeks the HbA1c was reduced from a mean baseline of 8.5% to 7.7%, 7.9% and 7.5% for the AIR, IG and AIR+IG groups, respectively. AIR produced a 0.2% greater decrease in HbA1c than IG. AIR+IG had a 0.35% greater HbA1c decrease vs. IG (−0.57, −0.13). The −0.15% difference between AIR+IG and AIR was not significant. More hypoglycaemia categorised as severe occurred with AIR alone vs. IG alone at LOCF end-points. More nocturnal hypoglycaemia occurred with IG alone vs. AIR alone and AIR+IG.

Conclusions: To apply inhaled insulin preprandially is an option for patients with type 2 diabetes not having optimal metabolic control with a long-acting insulin analogue. A number of aspects, like quality of metabolic control, hypoglycaemic risk, delivery preference and regimen complexity, must be considered when selecting the best insulin therapy to start with and optimisation regimens.

  • Comment: This interesting and large study was designed to compare three approaches for intensifying insulin therapy in patients with type 2 diabetes who did not achieve optimal control on once daily insulin glargine and OADs. After 24 weeks patients on inhaled insulin only had a larger change in metabolic control compared with patients on a long-acting insulin analogue alone. Combining prandial with basal insulin supply clearly further improved metabolic control, but without reaching significance vs. prandial insulin alone. However, one has to acknowledge that the quality of metabolic control achieved by many patients was not good; intensification of insulin therapy in this study was inadequate. Also study quality suffered from early termination due to the stopping of this inhaled insulin development.

Does availability of AIR insulin increase insulin use and improve glycaemic control in patients with type 2 diabetes?

R. M. Bergenstal,1N. Freemantle,2M. Leyk,3G. B. Cutler,3R. P. Hayes,3D. B. Muchmore3,4

1International Diabetes Center, Minneapolis, MN, USA,2University of Birmingham, Birmingham, UK,3Eli Lilly and Company, Indianapolis, IN, USA, and4Halozyme Therapeutics Inc., San Diego, CA, USA (present address)

Diabetes Technol Ther 2009; 11 (Suppl 2): S45–52

Background: The question studied was whether the availability of AIR inhaled insulin leads to greater initiation and maintenance of insulin therapy in patients with type 2 diabetes compared with existing treatment options alone. The idea is that when insulin therapy is going to be started the physician and the given patient discuss treatment options, explore the impact of treatment decisions from the patient’s perspective, and make treatment choices together. This might be different depending on the availability of inhaled insulin as a treatment option.

Methods: In a 9-month, multicentre, parallel, open-label study, adult non-smoking patients with diabetes not optimally controlled by two or more OADs were randomised to the standard options group (n = 516) or the standard options plus AIR insulin group (n = 505), in which patients had the same choices plus AIR insulin. The primary end-points were the proportion of patients in each group using insulin at end-point and change in HbA1c from baseline to end-point.

Results: At end-point, 53% of patients in the standard options group and 59% in the standard options plus AIR insulin group were using insulin (p = 0.07). Both groups improved metabolic control by about 1.2% and reported increased well-being and treatment satisfaction. The most common adverse event with AIR insulin was transient cough.

Conclusions: The increase in therapeutic options for insulin therapy by inhaled insulin did not affect overall use of insulin at end-point or metabolic control. Regardless of group assignment, the shared decision-making approach studied resulted in improved treatment satisfaction and metabolic control at end-point. Therefore, increasing patient involvement in treatment decisions may improve outcomes.

  • Comment: This ‘real world’ study in which patients had different options showed the interesting result that patients are not ‘jumping’ on a needle-free option as one would expect in view of the fact that many patients are reluctant to start insulin therapy. This indicates that it is not the ‘needle’per se– which is regarded more as the sign – but the insulin therapy in general that is the obstacle. The outcome of this study is different from that of a similar study performed before with EXU; however, there were a number of differences in details of the study design that might explain this. It is in line with the outcome of the previously discussed studies that also in this study AIR insulin was not associated with an improved metabolic control compared with SC insulin.

Safety and efficacy of AIR inhaled insulin compared with subcutaneous insulin in patients having diabetes and asthma: a 12-month, randomised, non-inferiority trial

E. Ang,1M. K. Lawrence,2C. R. Heilmann,3J. A. Ferguson,4J. A. Tobian,4D. M. Webb,4P. Y. Berclaz4

1Cardinal Santos Medical Center, San Juan, Philippines,2Down East Medical Associates, Morehead City, NC, USA,3US Medical Division, Lilly USA, LLC, and4Lilly Research Laboratories, Eli Lilly and Company, IN, USA

Diabetes Technol Ther 2009; 11 (Suppl 2): S35–44

Background: The aim of this study was to establish the long-term safety and efficacy of AIR insulin in patients with diabetes and asthma.

Methods: This was a 1-year, randomised, open-label, active comparator, two-arm, parallel study. In this the safety and efficacy of AIR insulin was compared with that of SC insulin in patients having type 1 or type 2 diabetes and asthma. Patients with type 2 diabetes continued to take their pre-study OADs.

Results: Change in HbA1c from baseline to end-point was similar for the AIR insulin and SC insulin groups, but non-inferiority failed to be achieved (upper limit of the 95% CI −0.053 to 0.555 was > 0.4%). Total daily prandial insulin dose increased more in the AIR insulin group than in the SC group (0.15 U/kg and 0.04 U/kg, respectively, p = 0.002). Safety profiles were generally comparable between treatments. At end-point, the ratio of Forced Expiratory Volume in 1 s to Forces Vital Capacity (FVC) post bronchodilator (−0.016 ± 0.005 vs. 0.002 ± 0.005, p = 0.006) and DCCO (−1.21 ± 0.33 vs. −0.38 ± 0.31 l/min/torr, p = 0.028) both decreased more in the AIR insulin group than in the SC group, but the differences were not present at follow-up. FEV1 and FVC were similar between treatment groups at end-point. Incidences of hypoglycaemia were comparable between groups. InsAb binding increased more in the AIR insulin group. The most common adverse event was cough; however, there was no difference in incidence between the AIR group and SC group.

Conclusions: AIR insulin demonstrated glycaemic efficacy similar to SC insulin in patients who have diabetes and asthma. Also the safety profile of AIR insulin in patients with and without asthma is consistent.

  • Comment: It is not easy to recruit a considerable number of patients with diabetes who also have asthma for a clinical study; however, the relatively large number of patients that discontinued (42 SC insulin, 39 AIR insulin) is a limitation of this study. The main reason for this was the sponsor decision to terminate the development of the AIR insulin system. In that sense this is an important study with inhaled insulin that adds to the limited data available on this subgroup of patients.

Inhaled insulin – technosphere

  1. Top of page
  2. Abstract
  3. Inhaled insulin
  4. Inhaled insulin – Exubera
  5. Inhaled insulin – air insulin
  6. Inhaled insulin – technosphere
  7. Inhaled insulin – others
  8. Oral insulin
  9. Nasal insulin
  10. Buccal insulin
  11. Insulin pens
  12. Miscellaneous
  13. References

Prandial inhaled insulin plus basal insulin glargine versus twice daily biaspart insulin for type 2 diabetes: a multicentre randomised trial

J. Rosenstock,1D. L. Lorber,2L. Gnudi,3C. P. Howard,4D. W. Bilheimer,4P. C. Chang,4R. E. Petrucci,4A. H. Boss,4P. C. Richardson4

1Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA,2Diabetes Control Foundation Center, Flushing, NY, USA,3Unit of Metabolic Medicine, Cardiovascular Division, King’s College London, UK, and4MannKind Corporation, Valencia, CA, USA

Lancet 2010; 375: 2244–53

Background: Many patients with T2DM delay the start of their insulin therapy. In this study the efficacy and safety of prandial TI was compared with twice daily SC biaspart insulin injections.

Methods: In this randomised, open-label, parallel group study, 677 adult patients with type 2 diabetes and poor glycaemic control despite insulin therapy, with or without OADs, were enrolled from 10 countries. Patients were randomly allocated in a 1:1 ratio to receive 52 weeks’ treatment with prandial TI plus bedtime insulin glargine or twice daily pre-mixed biaspart insulin. The primary end-point was a comparison of change in HbA1c from baseline to week 52 between treatment groups; the non-inferiority margin was 0.4%.

Results: In all, 334 patients were allocated to TI plus insulin glargine, and 343 to biaspart insulin; after drop-out, 211 patients on TI and 237 on biaspart insulin were included in per-protocol analyses. Improvement in metabolic control with TI was similar and non-inferior to that with biaspart insulin. The between-group difference was 0.07% (SE 0.102, 95% CI −0.13 to 0.27). Patients had lower weight gain and fewer mild-to-moderate and severe hypoglycaemic events on TI than on biaspart insulin. The safety and tolerability profile was similar for both treatments, apart from increased occurrence of cough and change in pulmonary function in the group receiving TI.

Conclusions: This study addresses the efficacy and tolerability of use of TI in a wide variety of patients.

  • Comment: It is good to see that the improvement in metabolic control was comparable between the two groups; however, one wonders if it would not have been a better study design if patients in the control arm had used a rapid-acting insulin analogue and a long-acting insulin analogue instead of an insulin mixture (with 30% prandial insulin only). That more insulin was prevailing in the bloodstream early with the meals with TI in comparison to the SC insulin mixtures can be clearly seen in differences of the postprandial glycaemic excursions with the meal challenge tests. From a lower preprandial value the increase in glycaemia was smaller in the first 60–120 min with TI; interestingly enough the maximal blood glucose values reached after 120 min were comparable. Glycaemia declined more slowly thereafter with TI than with SC insulin. This observation can be interpreted as a too rapid decline in metabolic effect of TI after a meal. The insulin doses applied with the two different insulin administration routes are not easy to calculate and compare from the numbers given in the publication. However, with both insulin regimens a rapid initial improvement in metabolic control was observed, by 0.8% in 14 weeks. It is of interest to note that also with TI fasting blood glucose was lower than with SC insulin, acknowledging the impact that the SC applied insulin glargine could also have had on this parameter in this patient group. A relatively high number of patients dropped out with both types of insulin therapy in this study; there were also a high number of screening failures. Adverse events such as cough and changes in lung function with TI have also to be acknowledged. Despite some limitations, this 1-year study showed that use of TI as prandial insulin allows good to acceptable metabolic control to be achieved in many patients with type 2 diabetes with a reduced risk of hypoglycaemic events.

A review of inhaled Technosphere insulin

J. J. Neumiller,1R. K. Campbell,2L. D. Wood1

1Department of Pharmacotherapy, College of Pharmacy, Washington State University/Elder Services, Spokane, WA, USA, and2Department of Pharmacotherapy, Washington State University College of Pharmacy, Pullman, WA, USA

Ann Pharmacother 2010; 44: 1231–9 (See also Neumiller and Campbell (2)

Background: To review the pharmacology, pharmacokinetics, efficacy, safety and clinical use of TI.

Methods: A MEDLINE search (1966–March 2010) was conducted for English language papers using the terms AFREZZA, AFRESA, TI, pulmonary insulin and inhaled insulin. Abstracts from the American Diabetes Association and European Association for the Study of Diabetes annual meetings, presented in 2004–2009, were also searched for relevant data. English language papers pertinent to the pharmacology, pharmacokinetics, efficacy and safety of TI were reviewed.

Results: TI is an inhaled insulin product with a PK profile suitable to meet prandial insulin needs in patients with diabetes. TI has demonstrated efficacy in terms of postprandial and overall glycaemic control, with efficacy and safety outcomes maintained for up to 4 years in one study. The overall tolerability profile for TI in clinical trials published to date has demonstrated a relatively low risk of hypoglycaemia and weight gain compared with SC prandial insulins. Clinical trials to date have demonstrated safety in terms of pulmonary function, and the absorption of TI is not significantly altered in patients with chronic obstructive pulmonary disease or in those who smoke.

Conclusions: The Technosphere delivery system allows for the rapid absorption of TI via the lung, making this product a potential option for prandial insulin coverage in both type 1 and type 2 diabetes. The device to administer the insulin is well designed, small and easy to use. TI may provide a useful treatment option for patients resistant to or fearful of initiating prandial insulin injections.

  • Comment: This is a good review of the literature published about TI and worthwhile reading.

Effect of Technosphere inhaled insulin on quality of life and treatment satisfaction

M. Peyrot,1,2R. R. Rubin2,3

1Department of Sociology, Loyola University Maryland, Baltimore, MD, USA,2Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA, and3Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Diabetes Technol Ther 2010; 12: 49–55

Background: This randomised controlled trial assessed the impact of TI delivered via the MedTone inhaler on quality of life and treatment satisfaction in adults with type 2 diabetes.

Methods: Patients (n = 119) were insulin-naïve with starting HbA1c > 6.5%: 58 in the active inhaled insulin arm and 61 in the inhaled placebo arm. Subjects completed a measure of health-related quality of life (the SF-36) and a measure of treatment satisfaction [the Insulin Treatment Questionnaire (ITQ), which assesses diabetes worries, perceptions of insulin therapy, and inhaler performance] before starting insulin treatment and approximately 12 weeks later.

Results: No significant change was observed in any SF-36 factor or the ITQ during the trial in either arm. There were no between-arm differences in change of any of these measures. Perceptions of insulin therapy improved during the trial in the active medication arm (effect size for composite measure 0.56, p = 0.002) but not in the placebo arm; there were no significant between-arm differences in change. The majority of subjects gave positive ratings of inhaler performance on all items (median: 93% positive ratings).

Conclusions: Treatment with TI was well tolerated, clinically efficacious and associated with positive patient-reported outcomes, including improved attitudes toward insulin therapy and high treatment satisfaction. No negative impact on health-related quality of life or worries about diabetes was reported with this treatment.

  • Comment: Patient acceptance of a given new diagnostic or therapeutic option is of great relevance for its market success. In the abstract it is not stated that this was a double-blind study: active inhaled TI vs. placebo inhaled TI. Patients in the active TI group applied approximately 30 U TI (= 10 U SC insulin) per meal and had an improved metabolic control. One wonders if the patients in this group did not know that they were in the active group, simply by measuring blood glucose. This is of interest to keep in mind when interpreting the data reported, i.e. that there were no differences in SF-36 and the ITQ, but that perception of insulin therapy differs. Believing that the patients in the active group were happy with using TI and the inhaler, it would have been of interest to know what patients in an additional study arm would have stated if these had used a modern insulin pen for SC insulin therapy. In the Discussion section it is stated that such studies are on their way now. It appears that at least some patients were not too happy with the inhaler performance (see Table 5 of the publication) (3).

Inhaled insulin – others

  1. Top of page
  2. Abstract
  3. Inhaled insulin
  4. Inhaled insulin – Exubera
  5. Inhaled insulin – air insulin
  6. Inhaled insulin – technosphere
  7. Inhaled insulin – others
  8. Oral insulin
  9. Nasal insulin
  10. Buccal insulin
  11. Insulin pens
  12. Miscellaneous
  13. References

The effect of terbutaline on the absorption of pulmonary administered insulin in subjects with asthma

A. H. Petersen,1,2S. Korsatko,1G. Köhler1, A. Wutte,1H. Olschewski,1T. Sparre,3J. Råstam,3P. Wollmer,4T. R. Pieber1

1Medical University of Graz, Graz, Austria,2University of Aarhus, Aarhus, The Netherlands,3Novo Nordisk A/S, Bagsvaerd, Denmark, and4Lund University, Malmö, Sweden

Br J Clin Pharmacol 2010; 69: 271–8

Background: The aim of this study was to investigate the effect of prior administration of the bronchodilator terbutaline on the absorption of inhaled insulin in people with asthma treated with inhaled corticosteroids.

Methods: This randomised, open-label, two-period crossover trial was carried out in non-diabetic subjects (n = 41) with asthma treated with inhaled steroids: 25 with reversible bronchoconstriction (Rev+) and 16 without reversible bronchoconstriction (Rev−).

An insulin dose of 0.10 U/kg inhaled insulin was administered on each dosing day with or without prior administration of terbutaline.

Results: Administration of terbutaline led to a 44% increase in insulin absorption over 6 h for the subjects in the Rev+ group compared with no prior administration of bronchodilator (p = 0.004), whereas no effect was seen for the Rev− or the whole group. Maximal insulin levels (Cmax) increased by 34% for the Rev+ group (p = 0.018) and 17% for the whole group (p = 0.046), whereas no effect was seen for Rev−. Time to Cmax was not different for the Rev+ group, whereas it was approximately 30% longer after bronchodilator administration for the Rev− group (p = 0.044) and the whole group (p = 0.032).

Conclusions: Administration of a bronchodilator in people with asthma and reversible bronchoconstriction prior to administration of inhaled insulin led to increased absorption of insulin. In contrast, no effect on insulin absorption could be observed in subjects without significant reversibility.

  • Comment: As with each route of insulin administration, there are a number of aspects that are of clinical relevance when treating real patients. In the case of pulmonary insulin it is important to know what impact different types of lung diseases per se have on insulin absorption in the lung and also what impact the treatment of a given lung disease has on insulin absorption. The authors of the paper have performed a number of systematic investigations about practically relevant questions, e.g. about the impact of exercise on insulin absorption in the context of pulmonary insulin application. This study shows that not only does the bronchodilatation induced by a specific co-medication have an impact on insulin absorption, but also that the status of the disease (in this case asthma) is of relevance. This is important information for the diabetologist who is interested in treating his/her patients, who also have asthma, with inhaled insulin.

Oral insulin

  1. Top of page
  2. Abstract
  3. Inhaled insulin
  4. Inhaled insulin – Exubera
  5. Inhaled insulin – air insulin
  6. Inhaled insulin – technosphere
  7. Inhaled insulin – others
  8. Oral insulin
  9. Nasal insulin
  10. Buccal insulin
  11. Insulin pens
  12. Miscellaneous
  13. References

Each year a number of new approaches for OI are published in pharmaceutical journals. Usually in these studies the metabolic effects of a given OI are studied in a more or less large number of rats. In practically all of these publications, the same statement is used in the last sentence of the paper and this is that this OI is a ‘promising development’. However, only a very small number (if any at all!) of these approaches are transferred into clinical development.

In view of this fact it is of no surprise that only three original papers were published in the last year in which data from clinical–experimental studies in humans are presented. In contrast, the number of reviews published about this topic (four) is higher (two reviews focus more on clinical studies while the other two focus on important techniques for OI formulations). However, two of the original papers are from companies (Emisphere and Diabetology with their Capsulin development) which appear to have ‘limited activity’ in oral insulin development nowadays (see the respective homepages).

In contrast, Biocon is in phase 3 studies with IN-105. It will be of interest to see whether Biocon will focus on the large Indian market in the first step with their OI or whether they will also try to get market approval in the USA and EU, and whether the regulatory authorities will regard their OI as safe and effective. Also the small Israel-based company Oramed is quite active and in the late phase of clinical development. In contrast, Novo Nordisk is in an early development phase with their OI (NN-1952), which is a co-development with the Irish company Merrion Pharmaceuticals. There is a recent review about the pharmacological approach used with this OI; however, no human/clinical data are presented (4). The Chinese company Biolaxy has also announced that they are developing an OI and have performed pilot clinical studies with patients with type 2 diabetes, but no data have been presented so far. Other companies like Access Pharmaceuticals – which has an OI in which the insulin is bound to cobalamin (vitamin B12) – announced plans to initiate clinical trials; however, again no data have been presented so far.

Open-label study to assess the safety and pharmacodynamics of five oral insulin formulations in healthy subjects

R. Eldor,1M. Kidron,1,2E. Arbit2

1Diabetes Unit, Hadassah University Hospital, Jerusalem, Israel, and2Oramed Pharmaceuticals, Hi-Tech 2/5, Givat Ram, Jerusalem, Israel

Diabetes Obes Metab 2010; 12: 219–23

Background: The ability of OI to mimic the natural route of endogenous insulin secreted by the pancreas into the portal vein and directly to the liver is assumed to have therapeutic advantages in diabetes therapy compared to SC injected prandial insulin. Oramed Pharmaceuticals is developing an OI product which consists of unmodified recombinant human insulin combined with adjuvants that protect it from enzymatic degradation in the gastrointestinal tract and promote its absorption from the gut. The aim of this study was to determine the optimal ratio between adjuvants and insulin with respect to the best pharmacodynamic properties, while maintaining the safety of the product.

Methods: Eight healthy, male volunteers participated in this open-label study which included five study days. During each study day, the subjects swallowed one of the five encapsulated OI formulations which contained equal amounts of insulin but varying proportions of adjuvants. Parameters assessed included safety, Cmax and Tmax for insulin and Cmin, Tmin and area under the curve (AUC) for glucose and serum C-peptide. Comparisons were made between formulations and between post-treatment time periods within each visit.

Results: All five OI insulin formulations were well tolerated and no serious adverse events were reported. Also all formulations resulted in a significant response in the response period (60–300 min) in comparison to baseline (0–60 min); this was captured in both the serum C-peptide response and the blood glucose response (all formulations p < 0.05). None of the formulations turned out significantly different in response from the others. However, formulation five showed the highest reduction in C-peptide when AUC0–60 (baseline) was compared to AUC60–300 (p < 0.007).

Conclusions: All five OI formulations resulted in blood glucose and serum C-peptide reductions. Formulation five was deemed the lead formulation to be advanced to future clinical studies. This study demonstrated that OI maintains its biological activity after delivery, suggesting a potential role for insulin therapy.

  • Comment: In this small study eight healthy subjects swallowed capsules with different amounts of carrier and adjuvants (it is not stated which substances these are) and the decline in blood glucose/C-peptide levels was monitored. Unfortunately no individual profiles are provided, but a difficult to interpret table only. That all OI formulations showed a metabolic effect is positive; however, the question is how strong this will be in connection with a meal. One also wonders why c-peptide is not written as C-peptide as is done usually.

Glucose lowering effect of an oral insulin (Capsulin) during an isoglycaemic clamp study in persons with type 2 diabetes

S. D. Luzio,1G. Dunseath,1A. Lockett,2T. P. Broke-Smith,2R. R. New,2D. R. Owens1

1Diabetes Research Unit, University Hospital Llandough, Penarth, South Glamorgan, UK, and2Diabetology Ltd, London Bioscience Innovation Centre, London, UK

Diabetes Obes Metab 2010; 12: 82–7

Background: In this study the PK and PD properties of SC RHI and oral insulin in a capsule form (Capsulin) were compared.

Methods: This was a randomised, open, single-centre, two-way crossover study in adult patients (n = 16, 12 males) with type 2 diabetes on OADs [age 60.2 ± 5.5 years, body mass index (BMI) 28.3 ± 3.4 kg/m², HbA1c 7.4% ± 1.1%]. Two 6-h isoglycaemic glucose clamps were conducted 11 days apart. All patients received in random order 12 U RHI SC on one study day and either 150 U or 300 U Capsulin (Cap) on the other day. Glucose infusion rates (GIRs), plasma insulin and serum C-peptide levels were determined throughout each clamp. Between the clamp study days, all patients received 150 U Capsulin twice daily, dropping all their standard OADs apart from metformin. Self-monitored blood glucose levels were taken four times a day between the clamp study days.

Results: Administration of either RHI or Cap (150 and 300 U) slowly increased GIRs, reaching maximum values at approximately 280–330 min. Overall values for maximum GIR values were higher for RHI than either dose of Cap (p < 0.05). The greater systemic insulin concentrations following RHI were reflected in the AUC0–6 h (910 ± 270 vs. 472 ± 245 pmol h/l; 950 ± 446 vs. 433 ± 218 pmol h/l; both p < 0.05 for RHI vs. 150 U Cap and 300 U Cap, respectively). No difference was observed between 150 U and 300 U Cap. During the repeat-dosing period, good safety and tolerability were observed with Cap, and self-monitoring of blood glucose levels remained stable. At the post-study visit, significant falls in HbA1c, weight and triglycerides were observed.

Conclusions: Administration of the OI Capsulin preparation demonstrated a significant hypoglycaemic action over a period of 6 h, while circulating plasma insulin concentrations increased minimally.

  • Comment: After a number of inconclusive studies with this OI presented in previous years, this is the first full clinical–experimental study investigating the PK and PD properties of Capsulin. In contrast to other OIs, Capsulin shows a slow onset of the metabolic effect induced. The missing dose–response relationship (identical metabolic effect with 150 and 300 U) is puzzling. Also the findings that in the 10 days in which this OI was used for prandial insulin therapy blood glucose remained high (and that no hypoglycaemic events were observed) can be regarded as an indication of a low bioavailability/biopotency. Because of the degrading of insulin in the liver directly after absorption (and the control on hepatic glucose production this might induce), the correlation between PK and PD data with OI is not as close as with SC insulin administration.

Oral insulin: a comparison with subcutaneous regular human insulin in patients with type 2 diabetes

C. Kapitza,1E. Zijlstra,1L. Heinemann,1M. C. Castelli,2G. Riley,2T. Heise1

1Profil Institut für Stoffwechselforschung, Neuss, Germany, and2Emisphere Technologies, Cedar Knolls, NJ, USA

Diabetes Care 2010; 33: 1288–90

Background: The aim of this study was to determine the PK and PD properties of an OI compared with SC injected RHI.

Methods: Patients with type 2 diabetes (n = 10) with mean HbA1c 7.0 ± 1.1% received either 300 U of insulin combined with 400 mg of delivery agent orally or 15 IU RHI SC under isoglycaemic clamp conditions.

Results: Maximum serum insulin concentrations were higher and onset of action was faster with OI (Cmax 93 ± 71 vs. 33 ± 11 μU/ml; AUCGIR 0–1h 173 ± 86 vs. 27 ± 32 mg/kg; p < 0.05). Mean serum insulin levels and glucose infusion rate returned to baseline within 3 h after OI administration. Relative bioavailability of OI was 7% ± 4% (first 2 h).

Conclusions: OI has a rapid absorption (under fasting conditions), and it also led to a clinically relevant increase in glucose consumption. However, the inter-individual variability in insulin absorption/insulin action was considerable.

  • Comment: This study shows that under fasting conditions a significant amount of insulin was absorbed rapidly into the bloodstream after application of this OI. Subsequently also a rapid increase in glucose infusion rates was observed to keep blood glucose constant in this glucose clamp study. When the study was performed, this was the first PD proof that with OI a sufficient amount of insulin could be transferred into the bloodstream to cover prandial insulin requirements. In view of the fact that the euglycaemic glucose clamp technique provides the clearest (and unbiased) understanding of the PD properties of a given insulin formulation, this methodological approach should be used more systematically to study the PD properties of other OIs (and also other ARIAs). However, this study was performed some years ago and Emisphere is not developing this OI any further. The main reason for this is that in clinical trials performed under non-fasting conditions, the degree of insulin absorption with this OI was low in many subjects and quite variable. The intra- and inter-individual variability of insulin absorption is a key issue with any OI. It appears that this variability was not formally studied in any clinical study to date. It is of great practical relevance to understand which factors influence this variability with OIs.

Oral insulin – a review of current status

H. Iyer, A. Khedkar, M. Verma

R&D, Biocon Ltd, Bangalore, Karnataka, India

Diabetes Obes Metab 2010; 12: 179–85

If an OI formulation becomes available that works in daily practice, this would offer considerable advantages: it should improve patient convenience, provide rapid insulinisation of liver and adequate insulin delivery avoiding peripheral hyperinsulinaemia while potentially avoiding adverse effects of weight gain and hypoglycaemia. It is also evident that an earlier start of intensive insulin therapy accompanied by improved metabolic control results in substantial delay of the development of diabetes-related complications. All this makes an effective OI product very attractive for the management of patients with diabetes. However, despite decades of intensive work using a wide variety of technologies, until now no development of an OI formulation has been successful because of several barriers. This review summarises the development status of OI which is publicly reported to be undergoing clinical studies. Two OI products are currently in an advanced stage of clinical development. Data from the first study reporting long-term therapy with an OI are expected to be available in the second half of 2010.

  • Comment: This is an interesting review by the scientists that are the driving force behind the OI development at Biocon. After a short introduction to diabetes and diabetes treatment, the potential role of OI and ways to develop OIs are presented. As well as covering the different OI technologies they also provide an overview about the different companies that are working in this area of research. Unfortunately they do not review their own development in great detail.

Efficacy of oral/buccal insulin in the treatment of diabetes mellitus

[Article in Spanish]

Z. Herrador Ortiz, A. Llanos Méndez

Agencia de Evaluación de Tecnologías Sanitarias de Andalucía, Sevilla, España

Aten Primaria 2010; 42: 316–21

Background: The aim of this review was to evaluate the efficacy and safety of administering oral/buccal insulin by an analysis of published studies.

Methods: Databases like MEDLINE, EMBASE, Scopus, Current Contents, Web of Science and Cochrane Library, and the European Drugs Agency, Food and Drug Administration, International Network of Technological Evaluation Agencies, European Network for New and Emerging Technologies (EuroScan) and gravel research registers were searched for this systematic review. Unfortunately only two clinical trials were found and in none of these studies is a head-to-head comparison between a given oral/buccal insulin and the standard treatment with SC injected insulin made.

Results: Buccal insulin produced a greater and earlier reduction in postprandial blood glucose excursion 30 min after insulin application in the intervention group compared with the control group (decrease of 55 mg/dl). Also the increase in serum insulin was different, i.e. higher maximal levels (98 vs. 65 μU/ml) were observed with buccal insulin. Postprandial blood glucose levels with OI were comparable with those obtained with SC injected insulin, despite the fact that higher maximum serum insulin levels were observed (110 ± 130 vs. 96.3 ± 69.7 μU/ml).

Conclusions: Oral/buccal insulin provides, at least, metabolic control that is similar to that obtained with standard treatment. However, the studies have serious methodological problems of internal and external validity.

  • Comment: Employing a rigorous selection procedure resulted in a very small number of studies that the authors of this review were able to identify. They analysed these two papers in detail. It appears that they were not at all happy with the quality of the studies, a perception that is definitely true.

Design of oral insulin delivery systems

T. W. Wong

Particle Design Research Group, Faculty of Pharmacy, and Non-Destructive Biomedical and Pharmaceutical Research Centre, Universiti Teknologi MARA Malaysia, Puncak Alam, Selangor, Malaysia

J Drug Target 2010; 18: 79–92

Despite many years of research to replace the painful SC route of insulin administration, no OI is commercially available. Many different attempts, involving nanoparticles, microparticles, hydrogel, capsule, tablet and film patches were tested for OI delivery. These are usually formulated with polymeric adhesive, protease inhibitor, insulin aggregation inhibitor and functional excipients to improve transcellular, paracellular, Peyer’s patches, or receptor-mediated transport of insulin in gastrointestinal tract into the bloodstream. Superporous matrix, intestinal patches and charged-coupled micromagnet microparticles are other recent attempts to improve OI absorption. It is hoped that increasing the bioavailability of insulin can be achieved by having a formulation that emphasises an assembly of insulin and excipients in a physical structure which provides an element of drug targeting that maintains stability. In order to overcome the intestinal transport capacity limit muco-adhesiveness appears to be of importance to achieve a prolonged retention of dosage form in the intestinal tract. This translates into cumulative insulin release and absorption. Therefore, synthesis and use of muco-adhesive excipients, chemical modification of insulin to promote its physicochemical and biological stability for encapsulation in dosage form with prolonged retention characteristics and identification of potential insulin adjuncts are necessary efforts needed to accelerate the speed of obtaining a functional OI delivery system.

  • Comment: Ignoring the lengthy introduction about diabetes, diabetes therapy etc., this is a good, systematic and easy to read introduction into the different pharmacological options/techniques for OI formulation.

Challenges and advances in nanoparticle-based oral insulin delivery

R. M. Ramesan, C. P. Sharma

Biosurface Technology Division, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India

Expert Rev Med Devices 2009; 6: 665–76

The development of an OI formulation that works in daily practice has not been successful so far, despite rigorous efforts for many decades. However, our understanding of the development of biocompatible and biodegradable polymers, synthesis of nanopeptide delivery systems, biocompatibility and its cellular uptake mechanisms has evolved tremendously over the past few years. Therefore the development of nanoparticle-based oral peptide delivery systems seems to be feasible. Nanoparticles enhance bioavailability by facilitating insulin uptake into the bloodstream via a transcellular or paracellular pathway. Clearly, biocompatibility and the half-life of the particles in the bloodstream are of paramount relevance. In this review, the various approaches adopted for nanoparticle-based OI delivery, uptake mechanisms, biocompatibility and bioavailability of the nanoparticle are discussed.

  • Comment: This is another interesting review, focused more on the methodological aspects of OI development.

Nasal insulin

  1. Top of page
  2. Abstract
  3. Inhaled insulin
  4. Inhaled insulin – Exubera
  5. Inhaled insulin – air insulin
  6. Inhaled insulin – technosphere
  7. Inhaled insulin – others
  8. Oral insulin
  9. Nasal insulin
  10. Buccal insulin
  11. Insulin pens
  12. Miscellaneous
  13. References

Only one paper was published in the last year reporting about a clinical study in humans when insulin was applied to the nose. This publication is by the company CPEX (http://www.cpexpharma.com), which is a spinoff from Bentley. The company has also published in previous years about their ‘Nasulin’ development (which was in phase 2a), but according to a statement on their homepage the company is currently seeking to sell or out-licence their Nasulin programme. It appears that the number of companies that are active in this area of research has decreased in the last few years. However, as with OI, a number of papers (also reviews) were published in pharmaceutical journals about novel approaches for nasal insulin in the last year, but only reporting data obtained in rats.

Comparison pharmacokinetics of two concentrations (0.7% and 1.0%) of Nasulin, an ultra-rapid-acting intranasal insulin formulation

R. Stote,1T. Marbury,2L. Shi,3M. Miller,3P. Strange3

1CPEX Pharmaceuticals Inc., Exeter, NH, USA,2Orlanso Clinical Research Center, Orlando, FL, USA, and3Integrated Medical Development, West Windsor, NJ, USA

J Diabetes Sci Technol 2010; 4: 603–9

Background: The aim of this PK study was to characterise the dose response of two concentrations (0.7% and 1%) of a nasal insulin spray in healthy subjects. Additional dosing options of Nasulin would allow greater titration flexibility.

Method: A five-period crossover study was carried out with 24 healthy, non-smoking subjects. Subjects were in a fasted state for 5 h before and 45 min after administration for PK assessment and were then given a meal. Each spray contained 100 μl. Doses tested were 25, 35, 50, 70 and 100 U. Maximum concentration (Cmax) and AUC was estimated for each dose group.

Results: A dose response was demonstrated by baseline-adjusted Cmax of 22, 27, 56, 62 and 84 μU/ml for the 25, 35, 50, 70 and 100 U doses (p < 0.0001), respectively, and by baseline-adjusted AUC0–45 min values of 491, 592, 1231, 1310 and 1894 μU/ml/min (p < 0.0001). Glucose AUC0–45 min determinations also demonstrated a PD dose response.

Conclusions: PK and PD parameters showed proportional and linear dose responses with the two concentrations of Nasulin applied, making multiple doses available for clinical development.

  • Comment: A considerable number of subjects were studied for this pure PK study, which unfortunately was not a glucose clamp study to evaluate the PD properties at the same time. Only data from five of the eight study days are presented. It would have been of interest to learn how much time the application of the different insulin doses requires in practice. It appears that the different doses provide a linear relationship with the maximal plasma insulin levels, but with large inter-individual differences in the increase in insulinaemia observed. Nasal insulin application induces ‘adverse events (that) were probable administration site reactions and, in order of decreasing frequency, included application site irritation, sneezing, increased lacrimation, throat irritation, dysgeusia, headache, cough, nasal congestion, ocular hyperemia, nasal discharge, and mucosal paresthesia’.

Buccal insulin

  1. Top of page
  2. Abstract
  3. Inhaled insulin
  4. Inhaled insulin – Exubera
  5. Inhaled insulin – air insulin
  6. Inhaled insulin – technosphere
  7. Inhaled insulin – others
  8. Oral insulin
  9. Nasal insulin
  10. Buccal insulin
  11. Insulin pens
  12. Miscellaneous
  13. References

In contrast to the considerable number of press releases that Generex, the only company which is developing a buccal insulin formulation (Oral-lyn), has released in the last year and which have resulted in a lot of reports in the lay press and TV (http://www.generex.com), the number of scientific publications is limited (one review). This might be due to the fact that Oral-lyn has for some time now been in a large phase 3 trial and that all phase 1 and 2 studies have been completed (and published?). Most probably the company is currently preparing all documents that are necessary for submission to the regulatory authorities for market approval. The limited number of publications in this phase of clinical development of Oral-lyn is in contrast to, for example, the considerable number of papers published by MannKind about TI and cannot be attributed to a shortage of good scientists and people with excellent background in the pharmaceutical industry (e.g. Joseph Rubinfeld is their Chief Scientific Advisor). Generex was also able to secure a good source for the insulin needed – sanofi-aventis has signed a supply contract with them.

Review of clinical trials: update on oral insulin spray formulation

P. Pozzilli,1P. Raskin,2C. G. Parkin3

1Department of Endocrinology and Diabetes, University Campus Bio-Medico, Rome, Italy,2Department of Internal Medicine, Southwestern Medical Center at Dallas, Dallas, TX, USA, and3CGParkin Communications Inc., Carmel, IN, USA

Diabetes Obes Metab 2010; 12: 91–6

That an improvement in metabolic control has beneficial effects by reducing the risk of developing long-term microvascular complications was shown in patients with type 1 and type 2 diabetes. Improving metabolic control often requires use of multiple daily insulin injections (intensified insulin therapy). Unfortunately current methods of insulin administration are not optimal; many patients view insulin therapy as inconvenient and uncomfortable. Patients with type 2 diabetes in particular delay the start of insulin therapy because of this. OI administration (spraying insulin into the mouth to be absorbed via the buccal mucosa) provides an alternative to injectable and inhaled insulin. The system allows a liquid oral spray insulin formulation to be delivered into the mouth via an aerosol spray. The active pharmaceutical ingredient is recombinant human insulin. However, the time–action profile shows that this insulin formulation behaves more similarly to the rapid-acting insulin analogues. In clinical studies with healthy subjects and patients with type 1 and type 2 diabetes, the OI spray was absorbed in direct relation to the amount given and had a faster onset and a shorter duration of action compared with regular insulin injected SC. In all studies OI spray was generally well tolerated. Some healthy subjects and patients with type 1 diabetes experienced transient (1–2 min) mild dizziness during dosing; these symptoms were mild and self-limited. No other side effects were noted. The ease of use of the insulin spray formulation may increase patient acceptance and thereby enhance treatment compliance. Subsequently this potentially reduces complications and provides improved quality of life for patients with diabetes. This review provides an overview of the safety profile and proposed mechanism of action of this insulin formulation and presents findings from trials which studied its effects in patients with type 1 and type 2 diabetes.

  • Comment: When two well-known diabetologists write a review about a development that they are familiar with, the assumption is that they will provide a critical and detailed discussion of the data available about the mechanism of insulin absorption via the buccal mucosa and the clinical studies performed. In the short Discussion section of this review some critical remarks are made; however, in general this is more an overview of all published studies without an in-depth analysis.

Insulin pens

  1. Top of page
  2. Abstract
  3. Inhaled insulin
  4. Inhaled insulin – Exubera
  5. Inhaled insulin – air insulin
  6. Inhaled insulin – technosphere
  7. Inhaled insulin – others
  8. Oral insulin
  9. Nasal insulin
  10. Buccal insulin
  11. Insulin pens
  12. Miscellaneous
  13. References

That insulin pens have gained more scientific interest in recent years also reflects the important market share these devices have nowadays for SC insulin administration in many countries; the percentage of users also continues to grow in the USA. The first ‘reviews’ about this topic are published now (5) and supplement issues of journals focused on diabetes technology are filled by papers about insulin pens. As discussed before, practically all of these studies were sponsored by one of the manufacturers and in nearly all cases the product of the sponsor turned out to be ‘better’ than the other products studied.

Dosing accuracy of insulin pens versus conventional syringes and vials

Y. M. Luijf, J. H. DeVries

Department of Internal Medicine, Academic Medical Centre, Amsterdam, The Netherlands

Diabetes Technol Ther 2010; 12 (Suppl 1): S73–77

Background: In many countries insulin pens have acquired a pivotal role in insulin delivery, surpassing the use of syringes. The aim of this review was to determine differences in dosing accuracy between insulin pens and conventional syringes and vials.

Methods: A literature search in PubMed for relevant literature identified seven papers.

Results: The consensus was that pens are more accurate, especially at doses <5 IU. Pens tend to under-dose compared to syringes, but they do this with a high degree of consistency. No significant difference was found with respect to metabolic control in one study; however, fasting blood glucose levels decreased more in pen users compared to syringe users (p = 0.003). This study also showed that insulin pens improved health-related quality of life compared to syringes.

Conclusions: There is sufficient evidence to recommend the use of insulin pens when delivering doses <5 IU with respect to accuracy. For insulin doses >5 IU there is no clear benefit for the pen in terms of accuracy.

  • Comment: It is of note to see how low the number of publications is (n = 5) that deal with the accuracy of insulin pens (and there are many different pens on the market) compared with that of syringes. Also the methods used in the different studies differed considerably. The critical approach used in this review is something to keep in mind when reading other publications about this topic (see below).

Comparison of usability and patient preference for insulin pen needles produced with different production techniques: ‘thin-wall’ needles compared to ‘regular-wall’ needles: an open-label study

T. Siegmund, H. Blankenfeld, P. M. Schumm-Draeger

Clinic of Endocrinology, Diabetes and Vascular Medicine, Teaching Hospital Munich-Bogenhausen of the Technical University, Munich, Germany

Diabetes Technol Ther 2009; 11: 523–8

Background: The aim of this study was to evaluate if insulin pen needles that have ‘thin walls’, i.e. have the same outer diameter but a relatively larger inner diameter compared to needles produced with a ‘regular wall’, are different with respect to pen user habits as well as patient’s appraisals and ratings.

Methods: In this multicentre open-label, single-arm study with patients with diabetes mellitus (n = 97) two different types of 31-gauge pen needles were studied: ‘thin-wall’ needles vs. ‘regular-wall’. Patients use one type of needles for 2 weeks each, starting with a regular-wall period followed by a thin-wall period. After each period patients filled in questionnaires.

Results: Patients reported reduced pain, bleeding, skin irritation, injection strain, needle occlusion and insulin leakage from the needle tip after injection when using thin-wall needles (p < 0.001). Also a higher proportion of patients expressed an overall preference for the thin-wall needles compared with the regular-wall needles ((78% vs. 8%, p < 0.001).

Conclusions: It appears that thin-wall 31-gauge needles for insulin pens are more user-friendly and consequently preferred by the patients. Additional larger-scale trials using blinded and randomised study designs are needed to validate these findings.

  • Comment: The last sentence of the abstract of this paper is probably the key point. It might very well be that the larger inner diameter of the thin-wall needles has relevance for patients; however, one wonders if the outcome of this study would have been that positive if the study were performed in a blinded manner. It should be mandatory that all such studies (if this is possible) are performed with such a study design. This statement might sound trivial; however, in many (if not in most) an unblinded study design was employed.

Skin and subcutaneous adipose layer thickness in adults with diabetes at sites used for insulin injections: implications for needle length recommendations

M. A. Gibney, C. H. Arce, K. J. Byron, L. J. Hirsch

BD (Beckton, Dickinson and Company), Franklin Lakes, NJ, USA

Curr Med Res Opin 2010; 26: 1519–30

Background: Inadvertent intramuscular injections of insulin may increase pain and/or adversely affect glucose control. In this study the most appropriate needle length was measured in adults with diabetes (28% with type 1 diabetes), in relation to skin thickness (ST) and the distance to muscle fascia.

Methods: Adult patients aged 18–85 years of different ethnicity in the USA were divided into three BMI subgroups: < 25, 25–29.9 and > 30 kg/m². Each subject had ultrasound measurements of ST and subcutaneous adipose layer thickness (SCT) at four injection sites.

Results: Patients had a BMI of 19.4–64.5 kg/m². Multivariate analyses showed that body site, gender, BMI and race are statistically significant factors for ST, but effects were small. Thigh ST was <0.6 mm thinner than the buttocks. Differences of 10 kg/m² account for 0.2 mm ST variation. Mean SCT were arm 10.8 mm, thigh 10.4 mm, abdomen 13.9 mm and buttocks 15.4 mm. Females had 5.1 mm greater SCT. Differences of 10 kg/m² account for 4 mm SCT variation.

Conclusions: SCT has a wider range. Needles > 8 mm, inserted perpendicularly, may frequently apply insulin intramuscularly in limbs of males and those with BMI < 25 kg/m². With 90 ° insertion, needles of 4–5 mm enter the SC tissue with minimal risk of intramuscular injection in virtually all adults.

  • Comment: Interestingly, this is one of the first studies in which the ST was systematically evaluated by means of modern ultrasound methods and well-trained operators in a considerable number of patients with diabetes. The study provides relevant data for the selection of needle length depending on the preferred injection site in patients, and also in lean and obese subjects (range of BMI 19.6–64.5 kg/m²). The ST is just above 2 mm at most common injection sites, varying significantly with factors like BMI, gender, diabetes type, race etc. The SC thickness ranged from 10 mm in the thigh to 15 mm in the buttocks, clearly with a much higher inter-individual variability than the ST depending on BMI, gender and body site. Combining ST and SC thickness allows the ‘ideal’ needle length to be estimated without raising a skin fold and inserting at 90 ° or 45 °. With a 90 ° insertion and a needle length of 5 mm > 98% of all insertions will be in the SC tissue. With 12.7 mm the insulin would be delivered intramuscularly 45% of the time; even with a 45 ° insertion this would happen in 21% of insertions. Acknowledging that old studies using outdated methods to study insulin PK showed no impact if insulin was applied in deep or superficial SC levels, one would like to see such studies repeated with more appropriate PK and PD measurements.

Comparative glycaemic control, safety and patient ratings for a new 4 mm × 32 gauge insulin pen needle in adults with diabetes

L. J. Hirsch,1M. A. Gibney,1J. Albanese,1S. Qu,1K. Kassler-Taub1, L. J. Klaff,2T. S. Beiley3

1BD (Beckton Dickinson and Company), Franklin Lakes, NJ, USA,2Rainer Clinical Research Center, Renton, WA, USA, and3AMCR Institute, San Diego, CA, USA

Curr Med Res Opin 2010; 26: 1531–41

Background: In this study the safety, efficacy and patient ratings of a new 4 mm × 32 gauge pen needle for SC insulin therapy were evaluated.

Methods: In total 173 patients with type 1 and type 2 diabetes and HbA1c 5.5%–9.5% participated in this randomised non-inferiority crossover trial. Patients used 4 mm × 32 gauge pen needles and either 5 mm × 31 gauge pen needles or 8 mm × 31 gauge pen needles in two 3-week treatment periods; order of needle use was controlled. Patients were either ‘low dose’ or ‘regular dose’ users (highest single insulin dose <20 U and 21–40 U, respectively). Percentage absolute change in serum fructosamine was the primary end-point.

Results: Of the 168 patients who completed the study, 163 were included in the fructosamine analyses−83 and 80 in the 4/5 mm and 4/8 mm groups, respectively. Subjects were 56% male, mean 52.6 years, 63% type 2, HbA1c 7.5% ± 1.0% and fructosamine 301 ± 55 mmol/l. Change in percentage fructosamine was 4.9% and 5.5%, respectively, for the 4/5 mm and 4/8 mm groups, meeting glycaemic equivalence criteria; results were similar in both dose groups. Unexplained severe hypoglycaemic and hyperglycaemic episodes were infrequent and not different between pen needles. The 4 mm pen needle was rated significantly less painful and preferred by approximately two-thirds of subjects (p < 0.01). All three pen needles had similar reported injection site leakage.

Conclusions: The 4 mm × 32 gauge pen needle provided equivalent metabolic control to the 31 gauge 5 mm and 8 mm pen needles with reduced pain and was preferred by patients.

  • Comment: Not too many studies have been published so far that compare the impact of needle length on metabolic control and on patient preference; most of these are ‘old’ (published > 10 years ago) and focused on PK and not on PD parameters. It is impressive to see that the 4-mm needle length has such an impact on a number of parameters, especially on pain, not so much on metabolic control. The difference in pain might be explained not only by the different length, but also by the difference in diameter. Knowing that the majority of patients today use an 8 mm needle, one wonders if patients will switch to one that has just half the length. Clearly one would like to see this study repeated with a longer study duration (focusing on HbA1c) and in different patient groups, and also in different countries.

The best insulin injection pen device for caregivers: results of injection trials using five insulin injection devices

F. Yakushiji,1H. Fujita,2Y. Terayama,3M. Yasuda,1K. Nagasawa,4M. Shimojo,5K. Taniguchi,1K. Fujiki,1J. Tomiyama,1H. Kinoshita1

1Department of Internal Medicine, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan,2Department of Transfusion Medicine, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan,3Department of Pharmacy, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan,4Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan, and5Department of Internal Medicine, Kanagawa Prefectural Shiomidai Hospital, Kanagawa, Japan

Diabetes Technol Ther 2010; 12: 143–8

Background: Insulin pens are primarily used by patients with diabetes. However, because of demographic changes there are an increased number of patients who cannot self-inject insulin. In such cases the insulin is applied by caregivers (‘other-injection’). The aim of this study was to evaluate insulin pens for ‘other-injection’ use.

Methods: Five devices – OptiClik (sanofi-aventis, Paris, France), SoloSTAR (sanofi-aventis), MirioPen without an antiskid tool (Eli Lilly, Indianapolis, IN), MirioPen with an antiskid tool (Eli Lilly, Hyogo, Japan) and FlexPen® (Novo Nordisk, Bagsværd, Denmark) – were evaluated. Twenty-two respondents (age 43 ± 9 years) injected themselves (self-injection) and others (other-injection). They evaluated the ease of use and feel of the pen devices via questionnaires.

Results: For self-injection FlexPen was selected as the best device but as the worst for other-injection. OptiClik was selected as the second worst device for self-injection but as the best device for other-injection. Moreover, for other-injection, FlexPen was too long and less stable, had poor dial visibility, was difficult to recap, and was comprehensively inferior.

Conclusions: Caregivers identified problems that were not apparent during studies with patients with diabetes. Devices meant for other-injection should have different features from those designed for self-injection.

  • Comment: In a world with a rapidly aging population (focusing on industrialised countries), the number of patients that live at home but require daily medical support is also increasing rapidly. Not only does this induce a massive increase in costs, but it is an aspect that diagnostics and pharmaceutical companies do not have in their focus when developing new options for diabetes therapy. However, as this study shows, interesting differences in the preference of caregivers exist with respect to different insulin pens. It is of note which aspects are of relevance for them: ‘FlexPen was too long, less stable, had poor dial visibility, was difficult to recap, and was comprehensively inferior’. Interestingly, the FlexPen has a length of 140 mm, whereas that of OptiClik is 167 mm.

Lessons learned during the development of HumaPen Memoir, an insulin pen with a memory feature

S. D. Breslin,1D. A. Ignaut,2D. E. Boyd3

1Delivery Device Research and Development, Eli Lilly and Company, Indianapolis, IN, USA,2Diabetes/Endocrine Medical, Eli Lilly and Company, Indianapolis, IN, USA, and3Medical Device Solutions, Battelle Memorial Institute, Columbus, OH, USA

J Diabetes Sci Technol 2010; 4: 540–6

The major advantages of insulin pens are their ease of use, portability and discreetness. The development of new insulin pens can pose significant challenges to the development team in that they must balance substantial accuracy requirements with aesthetic desires. The lessons learned by a team that developed the HumaPen Memoir throughout the development process are described. The team must decide whether to use a quality functional deployment or a system-engineering-based development plan. Additionally, they have to recognise where proof of concept ends and product development begins to maintain a strict timeline for the project. In order to ensure a timely and high-quality product launch to the marketplace, a proficiency in understanding and managing technical risk is critical.

  • Comment: Many people believe that the development of a new medical device (an insulin pen in this case) is something a group of good engineers can easily handle in 3 months. In other words, construction of some simple plastic pieces appears to be a relatively simple and straightforward task. Reading this paper might be an eye-opener to many people. It is intriguing to read how complex and time demanding such a development is in reality. Unfortunately, these are aspects companies normally do not report. It is worth noting that the team which developed this new insulin pen with an electronic memory was often near the bleeding edge with certain aspects of the design.

Dose accuracy of SoloSTAR and FlexPen as assessed in a clinical setting

A. Friedrichs

LWS Risk Management Consult GmbH, Brannenburg, Germany

Diabetes Technol Ther 2009; 11: 609–13

Background: The aim of this study was to compare the accuracy of SoloSTAR (sanofi-aventis) and FlexPen (Novo Nordisk) to deliver doses of insulin when used by insulin/device-naïve people.

Methods: For determination of dose accuracy, SoloSTAR containing insulin glargine and FlexPen containing insulin aspart were used for all tests. The participants received instructions by an independent monitor on how to use the pens and were trained to hold the pens in situ for 10 s at the end of injection to ensure that the full dose was injected. With each pen type the 48 subjects performed three dose deliveries of 20 U into a sponge.

Results: The delivery of 144 individual doses of 20 U was no different (p = 0.187) between SoloSTAR (19.8 ± 0.3 U) and FlexPen (19.8 ± 0.3 U). However, 2% of doses from both devices were < 19 U; 98% were within 19–21 units.

Conclusions: Both insulin pens were similarly accurate when used by device-naïve subjects to deliver insulin.

  • Comment: The interesting aspect of this evaluation is that it was not performed in a hospital/academic setting but in a local healthcare practice in Germany. The criticism of many practitioners is that such studies are usually performed in specialised centres and not under the conditions of daily care in a busy practice. Clearly one can challenge a number of aspects of study performance in this study; however, it would be worth performing such evaluations in practices treating patients every day as well. Reading the Author Disclosure Statement and who has supported the study makes clear why, despite the fact that no significant differences were observed, some positive sentences for one of the two pens show up in the Conclusion section; one can clearly foresee that these will show up in the marketing activities for this pen.

Miscellaneous

  1. Top of page
  2. Abstract
  3. Inhaled insulin
  4. Inhaled insulin – Exubera
  5. Inhaled insulin – air insulin
  6. Inhaled insulin – technosphere
  7. Inhaled insulin – others
  8. Oral insulin
  9. Nasal insulin
  10. Buccal insulin
  11. Insulin pens
  12. Miscellaneous
  13. References

The following three papers do not refer to new ways to deliver insulin in the strict sense. However, two present interesting new approaches to improve insulin absorption from the SC tissue by either increasing local blood flow as a reaction induced by heat applied to the skin for some minutes after insulin administration or by injecting the insulin not into the SC compartment but in the skin. With both approaches a significantly more rapid increase in insulinaemia and onset of metabolic effect could be observed compared to the control situation. Such improved PD properties should enable a better postprandial glycaemic control.

In the end, it is the willingness of the patients (and/or of the healthcare funds) to pay for new ways of insulin delivery that counts, i.e. without a commercial success none of the novel developments will survive once they are able to make it to the market. However, such aspects have gained not too much attention in the past (at least not much was published about such studies).

Minimally invasive insulin delivery in subjects with type 1 diabetes using hollow microneedles

J. Gupta,1,2E. I. Felner,1,2M. R. Prausnitz1,3

1School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, USA,2Department of Pediatrics, Division of Endocrinology, Emory University School of Medicine, Atlanta, GA, USA, and3Wallach J Coulter Department of Biomedical Engineering, Emory University School of Medicine, Atlanta, GA, USA

Diabetes Technol Ther 2009; 11: 329–37

Background: The aim of this study was to investigate if insulin delivery into human skin is possible by microneedles. Previously they have only been studied in animal models. The study hypothesis was that hollow microneedles allow a sufficient amount of insulin to be delivered to patients with type 1 diabetes.

Methods: In two adult patients with type 1 diabetes insulin lispro was applied as a bolus using a hollow microneedle compared to a catheter infusion set (9 mm needle length). In order to determine the minimum depth of microneedle insertion, these were inserted 1, 3.5 and 5 mm into the skin of the fasting patients. It was also studied if, with an insertion depth of 1 mm of the microneedles, a reduction in postprandial glycaemic excursions could be induced.

Results: Microneedles inserted at the shallowest depth of 1 mm within the skin already led to rapid insulin absorption and reduction in blood glucose levels. Bolus insulin delivery via the microneedles prior to consumption of a standardised meal showed that this route of insulin administration is effective in reducing postprandial blood glucose levels. Patients reported no pain from microneedle insertion, and there were no adverse events.

Conclusions: Intradermal insulin delivery by means of hollow microneedles allowed bolus insulin to be effectively delivered to patients with type 1 diabetes.

  • Comment: It is impressive to see that even with a sample size of n = 2 it is possible to get a paper accepted in a peer-reviewed journal. Intradermal application of insulin has been tested before; already these previous PK and PD studies have shown that with application in this compartment a more rapid absorption/action than with SC application is possible. However, the needles used in the studies were very short conventional needles, i.e. with a length of 1.5 mm. The needles used in this (micro-) study were glass pipettes. The insulin was applied by means of a syringe pump, i.e. the insulin was infused and not injected. The interesting data presented in this preliminary study should be reproduced in a formal clinical study.

Effect of a local heating device on insulin and glucose pharmacokinetic profiles in an open-label, randomised, two-period, one-way crossover study in patients with type 1 diabetes using continuous subcutaneous insulin infusion

I. Raz,1R. Weiss,1Y. Yegorchikov,2G. Bitton,2R. Nagar,2B. Pesach2

1The Diabetes Center, Hadassah Hebrew University School of Medicine, Jerusalem, Israel, and2Insuline Medical Ltd, Petah Tikva, Israel

Clin Ther 2009; 31: 980–7

Background: Improvement of postprandial glycaemic control is of great interest for patients with diabetes. Previous studies have shown that local heating of the insulin injection site accelerates insulin absorption by increasing local blood flow. The aim of this study was to assess the effect of local heating by means of the InsuPatch (InsuLine Medical Ltd, Petach-Tikva, Israel) on PK properties of a rapid-acting insulin analogue and on postprandial glycaemia.

Methods: This was an open-label, randomised, one-way crossover study using a meal tolerance test (MTT) protocol in patients with type 1 diabetes mellitus (n = 17) treated with continuous subcutaneous insulin infusion. An insulin bolus of 0.15 U/kg was applied prior to a standardised liquid meal.

Results: The postprandial glucose excursions (AUC0–120 min) were reduced in the group of patients that used the device compared with those that did not (104 ± 65 vs. 155 ± 56 mg/dl/h; p < 0.005). The PK data were assessed in nine subjects. With local heating, time to maximal insulin levels was reduced (tmax 45 ± 28 vs. 78 ± 35 min) and time to half-maximum levels as well (t50%max 20 ± 11 vs. 28 ± 10 min; both p < 0.05). Cmax also increased (118 ± 35 vs. 86 ± 16 mU/l; p < 0.05).

Conclusion: Local heating was associated with improved PK properties of an SC infused rapid-acting insulin analogue, resulting in a lower postprandial glucose excursion.

  • Comment: That local warming of the skin above the injection site improves insulin absorption has been known for decades. However, this is the first time that an attempt has been made to develop a system/device that can be used routinely in daily life by patients with diabetes. One interesting question, how much it is the blood flow in the dermis that is altered and not the flow in the SC compartment, remains to be studied. The effect of heating of the skin might have a different influence on the blood flow in these two compartments. An additional question is, if the nerve control of both compartments is known to be different, how much do environmental effects impact the effect of local heating on insulin absorption? In other words, what is the intra- and inter-individual variability of the induced increase in blood flow? The study presented in this publication has some shortcomings, e.g. PK data were not obtained for all subjects (also not completely for those in whom blood samples for PK measurements were collected), but the message is clear.

Socioeconomic differences in preferences and willingness-to-pay for insulin delivery systems in type 1 and type 2 diabetes

C. Guimarães,1,2C. A. Marra,2L. Colley,2S. Gill,2S. Simpson,3G. Meneilly,2R. H. Queiroz,1L. D. Lynd2

1University of São Paulo, São Paulo, Brazil,2University of British Columbia, Vancouver, BC, Canada, and3University of Alberta, Edmonton, AB, Canada

Diabetes Technol Ther 2009; 11: 567–73

Background: Unfortunately most often patients’ preferences are not taken into account when different insulin delivery systems are discussed. This study was performed to investigate the association between socioeconomic status (SES) and patients’ preferences and willingness to pay (WTP) for various attributes of insulin administration for diabetes management.

Methods: By means of a discrete choice experiment patients’ preferences and their WTP for hypothetical insulin treatments were determined. Differences in treatment preferences and WTP for different attributes of treatment across different levels of SES were explored by means of self-reported annual household income and education completed.

Results: In total 274 patients successfully completed the discrete choice experiment questionnaire. Overall, metabolic control was the most valued attribute by all socioeconomic groups. In contrast, the route of insulin delivery was not as important. Not surprisingly patients with higher incomes were willing to pay significantly more for better metabolic control and to avoid adverse events compared with lower income groups. They were also willing to pay more for an oral rapid-acting insulin compared with the low income group (p < 0.01). However, there were no differences in preferences when the sample was stratified by level of education.

Conclusions: This study showed that preferences and WTP for insulin therapy are influenced by income but not by level of education. Interestingly, the higher the income, the greater desire for an oral insulin delivery system, whereas an inhaled route becomes less important for patients.

  • Comment: One has the impression that many devices for diagnostic and therapeutic purposes are developed by excellent engineers and scientists, but not in close communication with patients with diabetes. However, in the end the patients have to use these devices 24/7. Ideally such devices would be designed in a manner such that the patients do not regard them as medical devices anymore but as lifestyle devices like modern cell phones. Also, with ARIAs the key question is, are the (potential) advantages of these approaches so profound that patients will be willing to pay some extra for them? To evaluate such aspects is not a trivial undertaking; however, in this study the authors present quite interesting data in this respect. In the end such evaluations should be an integrated part of each new development. Let us wait and see if patients are willing to pay extra – as an example for a novel inhaled insulin with improved PK/PD properties (= Technosphere insulin) – or not.

References

  1. Top of page
  2. Abstract
  3. Inhaled insulin
  4. Inhaled insulin – Exubera
  5. Inhaled insulin – air insulin
  6. Inhaled insulin – technosphere
  7. Inhaled insulin – others
  8. Oral insulin
  9. Nasal insulin
  10. Buccal insulin
  11. Insulin pens
  12. Miscellaneous
  13. References
  • 1
    Rosenstock J, Lorber DL, Gnudi L, Howard CP, Bilheimer DW, Chang PC, Petrucci RE, Boss AH, Richardson PC. Prandial inhaled insulin plus basal insulin glargine versus twice daily biaspart insulin for type 2 diabetes: a multicentre randomised trial. Lancet 2010; 375: 224453.
  • 2
    Neumiller JJ, Campbell RK. Technosphere insulin: an inhaled prandial insulin product. BioDrugs 2010; 24: 16572.
  • 3
    Rubin RR, Peyrot M. Psychometric properties of an instrument for assessing the experience of patients treated with inhaled insulin: the Inhaled Insulin Treatment Questionnaire (IITQ). Health and Quality of Life Outcomes 2010; 8: 32.
  • 4
    Maher S, Leonard TW, Jacobsen J, Brayden DJ. Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic. Adv Drug Deliv Rev 2009; 61: 142749.
  • 5
    Pearson T. Practical aspects of insulin pen devices. J Diabetes Sci Technol 2010; 4: 52231.