Abstract
Introduction
James Collip and Charles Best sold the insulin patent to the University of Toronto for only $1.00 (USD). They wanted everyone who needed their drug to be able to afford it. List prices of insulin in the United States have nearly tripled from 2002 to 2013, according to a report from a working group at the American Diabetes Association (1). This problem is certainly not limited to the United States and reasons for this increase are not entirely clear but are due in part to the complexity of drug pricing in general and of insulin pricing in particular. Worldwide, some patients are still rationing their insulin because taking too little is better than having none to take at all. While reducing insulin prices is important, on the other hand, we need to encourage innovation in the development of more effective (and affordable) insulin preparations. The question of who is to blame for skyrocketing insulin prices and what can be done about it does not have simple answers. In May 2019 the state of Colorado in the United States took the unusual step of capping the price of insulin in the state: the new law says people with diabetes independent of their insulin requirement will have a maximum co‐pay of $100 per month, regardless of how much they use, starting in January 2020.
One potential way to reduce cost is the development of biosimilars. Regulatory processes are likely to change next year in the United States, and it will be interesting to see if this leads to a change in the use of these products. Progress has been made evaluating the clinical use of new insulin products. In 2018–2019 the first data comparing glargine U300 and degludec have been published questioning differences between the two drugs in type 2 diabetes. However, it is still unclear whether there are any clinically meaningful differences between the two preparations in type 1 diabetes. Textbooks may need to be rewritten, in consideration of another approach to insulin therapy, as oral insulin may become a reality in the treatment of type 2 diabetes.
Regarding the ultra‐rapid mealtime insulin faster aspart, the remaining data from the clinical onset trial program was published in 2019. Of note, while the results of the adult onset®5 pump trial were controversial, the pediatric onset®7 trial revealed mealtime faster aspart providing superior control of glycated hemoglobin (HbA1c) compared with insulin aspart (IAsp). Unfortunately, the intended pediatric faster acting insulin aspart onset®6 pump trial was not conducted, as apparently such a study was not required for regulatory purposes.
Additional clinical data of Adocia's ultra‐rapid insulin, known as BioChaperone Lispro, were published also this year, but the commercial future of this product remains unclear. Recently, Adocia announced the first trial to test BioChaperone Lispro using an automated insulin delivery system, namely the Beta Bionics iLetTM in a multi‐arm, crossover, U.S.–only clinical trial, recruiting up to 30 people with type 1 diabetes to participate in three 7‐day study arms comparing the pharmacokinetic and pharmacodynamic profiles between and within subjects of insulin lispro, insulin aspart, and BioChaperone Lispro using the insulin‐only configuration of the iLet.
We are still waiting for the eventual publication of data on Eli Lilly's ultra‐rapid insulin Treprostinil Lispro (LY 900014). Several clinical trials have been registered, such as a phase 2 study in type‐1 diabetes (ClinicalTrials.gov identifier NCT03760640), the PRONTO‐compare phase 3 study in Europe (EudraCT2017‐003399‐30) or the PRONTO‐pump phase 3 trial (NCT03433677), which has been complete but not yet published.
In addition, academic research groups also contribute to the spectrum of new insulins. As in previous yearbooks, it has become a nice tradition to look at new concepts in the field of glucose‐responsive “smart insulins.” However, the clinical reality of this concept remains to be even further down the road.
Key Articles Reviewed for the Article
Rosenstock J, Cheng A, Ritzel R, Bosnyak Z, Devisme C, Cali AMG, Sieber J, Stella P, Wang X, Frias JP, Roussel R, Bolli GB
Sullivan SS
Tibaldi J, Hadley‐Brown M, Liebl A, Haldrup S, Sandberg V, Wolden ML, Rodbard HW
Pettus J, Roussel R, Zhou FZ, Bosnyak Z, Westerbacka J, Berria R, Jimenez J, Eliasson B, Hramiak I, Bailey T, Meneghini L
Madenidou A‐V, Paschos P, Karagiannis T, Katsoula A, Athanasiadou E, Kitsios K, Bekiari E, Matthews DR, Tsapas A
Halberg IB, Lyby K, Wassermann K, Heise T, Plum‐Mörschel L, Zijlstra E
Halberg IB, Lyby K, Wassermann K, Heise T, Zijlstra E, and Plum‐Mörschel L
Blevins TC, Barve A, Sun B, Ankersen M
Blevins TC, Barve A, Sun B, Raiter Y, Aubonnet P, Muniz R, Athalye S, Ankersen M Texas Diabetes and Endocrinology, Austin, TX; Mylan Inc., Canonsburg, PA, Mylan EPD,
Wang J, Yu J, Zhang Y, Kahkoska AR, Wang Z, Fang J, Whitelegge JP, Li S, Buse JB, Gu Z
Basu A, Pieber TR, Hansen AK, Sach‐Friedl S, Erichsen L, Basu R, Haahr H
Buse JB, Carlson AL, Komatsu M, Mosenzon O, Rose L, Liang B, Buchholtz K, Horio H, Kadowaki T
Klonoff DC, Evans ML, Lane W, Kempe HP, Renard E, DeVries JH, Graungaard T, Hyseni A, Gondolf T, Battelino T
Bode BW, Iotova V, Kovarenko M, Laffel LM, Rao PV, Deenadayalan S, Ekelund M, Larsen SF, Danne T
Pieber TR, Svehlikova E, Brunner M, Halberg IB, Due Thomsen KM, Haahr H
Andersen G, Meiffren G, Lamers D, DeVries JH, Ranson A, Seroussi C, Alluis B, Gaudier M, Soula O, Heise T
Meiffren G, Herbrand T, Anastassiadis E, Klein O, DeVries JH, Heise T, Alluis B, Mégret C, Gaudier M, Soula O, Plum‐Mörschel L
Heise T, Meiffren G, Alluis B, Seroussi C, Ranson A, Arrubla J, Correia J, Gaudier M, Soula O, Soula R, DeVries JH, Klein O, Bode B
Utlra‐Long‐Acting Insulin Analogs: Head‐to‐Head and Real‐World, Observational Comparisons between Insulin Glargine U300 and Insulin Degludec
More similarities than differences testing insulin glargine 300 units/mL versus insulin degludec 100 units/mL in insulin‐naïve type 2 diabetes: the randomized head‐to‐head BRIGHT trial
Rosenstock J1, Cheng A2, Ritzel R3, Bosnyak Z4, Devisme C5, Cali AMG6, Sieber J7, Stella P8, Wang X9, Frias JP10, Roussel R11,12,13, Bolli GB14
1Dallas Diabetes Research Center at Medical City, Dallas, TX; 2Division of Endocrinology and Metabolism, University of Toronto, Toronto, Canada; 3Klinikum Schwabing and Klinikum Bogenhausen, Städtisches Klinikum München GMBH, Munich, Germany; 4Sanofi, Paris, France; 5AIXAL, Boulogne‐Billancourt, France; 6Sanofi, Tokyo, Japan; 7Sanofi, Frankfurt, Germany; 8Sanofi, Budapest, Hungary; 9Sanofi, Beijing, China; 10National Research Institute; Los Angeles; CA; 11Diabetology Endocrinology Nutrition, Hôpital Bichat, DHU FIRE, Assistance Publique Hôpitaux de Paris, Paris, France; 12INSERM U‐1138, Centre de Recherche des Cordeliers, Paris, France; 13UFR de Médecine, Université Paris Diderot, Sorbonne Paris Cité, Paris, France; 14Perugia University Medical School, Perugia, Italy
Background
The BRIGHT trial is the first published, clinical head‐to‐head comparison between the two second‐generation longer‐acting insulin analogs; insulin glargine 300 units/mL (Gla‐300) and insulin degludec 100 units/mL (IDeg‐100).
Methods
A multicenter, open‐label, active‐controlled, two‐arm, parallel‐group, noninferiority study was carried out over 24 weeks in insulin‐naïve adults with less well controlled type 2 diabetes [HbA1c 7.5%–10.5% (58–91 mmol/mol)] on oral agents±GLP‐1 RAs. The participants were randomized 1:1 to receive an evening dose of Gla‐300 (n=466) or IDeg‐100 (n=463), titrated to self‐monitored, fasting plasma glucose between 80–100 mg/dL. The primary endpoint was change of HbA1c from baseline to week 24. Safety endpoints included incidence and event rates of hypoglycemia.
Results
In the Gla‐300 group, HbA1c was reduced from 8.7% (72 mmol/mol) at baseline to 7.0% (53 mmol/mol) at week 24, and in the IDeg‐100 group from 8.6% (70 mmol/mol) to 7.0% (53 mmol/mol); the least squares mean difference being −0.05% (95% CI −0.15 to 0.05) (−0.6 mmol/mol [95% CI −1.7 to 0.6]), demonstrating noninferiority of Gla‐300 versus IDeg‐100 (P<0.0001). Measures of hypoglycemia incidence and event rates over the full 24‐week period were similar with both insulin analogs, whereas during the titration period (0–12 weeks) the incidence and event rates of anytime (24 hour) confirmed hypoglycemia (≤ 70 and <54 mg/dL, respectively) were lower with Gla‐300 than with IDeg‐100.
Conclusions
Similar improvements in glycemic control were achieved with Gla‐300 and IDeg‐100. Hypoglycemia incidence and event rates were comparable with both insulin analogs during the complete 24‐week study period, but less evident with Gla‐300 during the titration period.
Comparable glycemic control and hypoglycaemia in adults with type 2 diabetes after initiating insulin glargine 300 units/mL or insulin degludec: the DELIVER Naïve D real‐world study
Sullivan SS1, Nicholls CJ2, Gupta RA3, Menon AA3, Wu J4, Westerbacka J5, Bosnyak Z5, Frias JP6, Bailey TS7
1The CHOICE Institute, School of Pharmacy, University of Washington, Seattle, WA; 2Sanofi, Guildford, UK; 3Accenture, Florham Park, New Jersey; 4Sanofi, Bridgewater, NJ; 5Sanofi, Paris, France; 6National Research Institute, Los Angeles, CA; 7AMCR Institute, Escondido, CA
Background
In this retrospective observational study, glycemic control, hypoglycemic events, and treatment discontinuation were assessed in insulin‐naïve adults with type 2 diabetes who had initiated basal insulin therapy with insulin glargine 300 units/mL (Gla‐300) or insulin degludec (IDeg).
Methods
Insulin‐naïve adults with type 2 diabetes who had started Gla‐300 or IDeg therapy between March 2015 and September 2017 were identified from electronic medical records from the IBM Watson Health Explorys database. Included patients had been active in the system for ≥12 months prior to and ≥6 months after starting Gla‐300 or IDeg and had registered HbA1c measurements during 6‐months baseline and at 3‐ to 6‐month follow‐up. Outcomes were compared among 1:1 propensity score–matched cohorts.
Results
In the matched cohorts (n=638 each), mean age was 59 years, 53% were male, and mean HbA1c was 9.67% (82 mmol/mol). The mean (SD) reduction in HbA1c was 1.67% (2.22) with Gla‐300 and 1.58% (2.20) with IDeg (P=0.51). HbA1c target attainment was also similar with both analogs; (HbA1c <7% [53 mmol/mol]: 23.8% vs. 27.4% [P=0.20]; HbA1c <8% [64 mmol/mol]: 55.0% vs. 57.1% [P=0.63]). Treatment discontinuation was 29.2% with Gla‐300 and 32.6% with IDeg [P=0.14]. Incidence and event rates of hypoglycemia [overall and inpatient/emergency department–associated hypoglycemia] were comparable in the two cohorts using either fixed 6‐month or variable on‐treatment follow‐up periods.
Conclusions
This real‐world observational study in insulin‐naïve adults with type 2 diabetes showed similar improvements in glycemic control and comparable rates of hypoglycemia after initiation of basal insulin therapy with Gla‐300 or IDeg.
A comparative effectiveness study of degludec and insulin glargine 300 U/mL in insulin‐naïve patients with type 2 diabetes
Tibaldi J1, Hadley‐Brown M2, Liebl A3, Haldrup S4, Sandberg V4, Wolden ML4, Rodbard HW5
1Fresh Meadows Diabetes and Endocrinology, New York, NY; 2School Lane Surgery, Thetford, Norfolk Primary Care Trust, Norfolk, UK; 3Centre for Diabetes and Metabolism, Fachklinik Bad Heilbrunn, Bad Heilbrunn, Germany; 4Market Access, Novo Nordisk A/S, Søborg, Denmark; 5Clinical Research, Endocrine and Metabolic Consultations, Rockville, MD
Background
A noninterventional, observational study comparing the effectiveness of insulin degludec and insulin glargine 300 U/mL in insulin‐naïve adults with type 2 diabetes.
Methods
Data were extracted from electronic medical records from the Explorys (IBM Watson Health) U.S. database, collected from multiple healthcare systems/providers. Propensity score matching was used to control for confounding. Primary endpoint was change in HbA1c from baseline to 180 days of follow‐up, estimated by a repeated measure of covariance analysis with subject random effect. Change in rates of hypoglycemic events was estimated using binomial regression and change in relative proportions of patients experiencing hypoglycemia with logistic regression. Time to discontinuation of degludec or glargine U300 and initiation of another prescribed basal insulin was analyzed using a Cox proportional‐hazards model.
Results
The analyses included data from 4,056 adults. After propensity score matching (n=2,028 in each group), baseline characteristics were comparable. After 180 days of follow‐up, basal insulin therapy with degludec was associated with a greater improvement in HbA1c (estimated treatment difference −0.27%; P=0.03), larger reductions in change in rate of hypoglycemic events (rate ratio 0.70; P<0.05) and in the likelihood of experiencing hypoglycemia (odds ratio 0.64; P<0.01), as compared with glargine U300. A smaller proportion of patients discontinued treatment with degludec (13%) versus treatment with glargine U300 (21%) at follow‐up; (hazard ratio 0.73; P<0.001).
Conclusions
In this real‐world, comparative effectiveness study in insulin‐naïve adults with type 2 diabetes, significantly larger reductions in HbA1c and rates of and likelihood of hypoglycemia, as well as lower risk of treatment discontinuation, were shown in favor of insulin degludec vs. glargine U300.
Rates of hypoglycemia predicted in patients with type 2 diabetes on insulin glargine 300 U/mL versus first‐ and second‐generation basal insulin analogs: the real‐world LIGHTNING study
Pettus J1, Roussel R2,3,4, Zhou FZ5, Bosnyak Z6, Westerbacka J6, Berria R5, Jimenez J5, Eliasson B7, Hramiak I8, Bailey T9, Meneghini L10,11
1School of Medicine, University of California, San Diego, CA; 2Inserm U1138m Centre de Recherche Des Cordeliers, Paris, France; 3University Paris Diderot, Sorbonne, Paris Cite, Paris, France; 4Diabetology, Endocrinology and Nutrition Department, DHU FIRE, Hopital Bichat, AP‐HP, Paris, France; 5Sanofi, Bridgewater, NJ; 6Sanofi, Paris, France; 7Institute of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; 8Lawson Research Institute, University of Western Ontario, London, ON, Canada; 9AMCR Institute, Escondido, CA; 10Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, TX; 11Global Diabetes Program, Parkland Health & Hospital System, Dallas, TX
Background
The LIGHTNING study utilized propensity score matching and a novel predictive modeling approach with machine learning to predict and compare hypoglycemia rates in adults with type 2 diabetes on insulin glargine 300 units/mL (Gla‐300) with those using insulin glargine 100 units/mL (Gla‐100), insulin detemir (IDet), or insulin degludec (IDeg) as basal insulin therapy.
Methods
Data were collected from the Optum Humedica U.S. electronic health records database. Each period during which a subject used a specific basal insulin (“patient‐treatments”) was analyzed for patients initiating basal insulin therapy and for those who had switched from a prior basal insulin. The definition of severe hypoglycemia included International Classification of Diseases‐9/10 codes in connection with emergency department visits or hospital admission, plasma glucose measurements <54 mg/dL or natural language processing that identified hypoglycemia from clinical notes.
Results
More than 830,000 adults with type 2 diabetes receiving basal insulin therapy were identified in the database. Following selection, 198,198 patient treatments were accessible for predictive modeling, which showed that rates of severe hypoglycemia were about 50% lower with Gla‐300 than with Gla‐100 or IDet in insulin‐naïve subjects, and 30% lower versus IDet in those who had switched from another basal insulin therapy (P<0.05 in all comparisons). Similar rates of severe hypoglycemia were predicted for Gla‐300 and IDeg, in both insulin‐naïve individuals and basal insulin switchers. Propensity score matching performed on 153,573 patient treatments demonstrated similar improvements in HbA1c with Gla‐300 compared with the other basal insulins analogs, and lower rates of severe hypoglycemia with Gla‐300 versus Gla‐100 and IDet (P<0.05), and similar rates versus IDeg in insulin‐naïve subjects and switchers.
Conclusions
These observational findings provide additional support that rates of severe hypoglycemia are lower with Gla‐300 than with first‐generation basal insulin analogs and comparable to those with IDeg.
Comparative benefits and harms of basal insulin analogues for type 2 diabetes: a systematic review and network meta‐analysis
Madenidou A‐V1, Paschos P1, Karagiannis T1, Katsoula A1, Athanasiadou E1, Kitsios K1, Bekiari E1, Matthews DR2 , Tsapas A1
1Clinical Research and Evidence‐Based Medicine Unit, Aristotle University of Thessaloniki, Thessaloniki, Greece; 2Harris Manchester College, University of Oxford, Oxford, UK
Background
The aim of this study was to assess the efficacy and safety of existing basal insulin analogues by performing a network meta‐analysis of randomized controlled trials.
Methods
Randomized controlled trials lasting for at least 12 weeks and comparing the efficacy [change in HbA1c from baseline (primary outcome), HbA1c <7% target attainment, and change in body weight] and safety (hypoglycemia) of altogether 10 different basal insulin analogues were searched, and the final analysis included 39 trials with 26,195 participants.
Results
Estimates from the network meta‐analysis showed low‐ to very low‐quality evidence that thrice‐weekly degludec (Deg3TW) was inferior to most other analogue regimens in reducing HbA1c, with mean differences ranging from 0.21% [vs. degludec 100 U/mL (Deg‐100)] to 0.32% [vs. glargine 300 U/mL (Gla‐300)]. High‐ to moderately high‐quality evidence indicated that detemir had a more favorable weight profile than all other comparator analogues, and glargine 300 U/mL (Gla‐300) was associated with less weight gain versus glargine 100 U/mL (Gla‐100), degludec 100 U/mL (Deg‐100), degludec 200 U/mL (Deg‐200), Deg3TW, and biosimilar glargine 100 U/mL, respectively. Low‐ and very low‐quality evidence suggested that degludec (both Deg‐100 and Deg‐200) and Gla‐300 were associated with lower incidence of nocturnal hypoglycemia than detemir, Gla‐100, biosimilar glargine, and neutral protamine lyspro (NPL). Frequency of severe hypoglycemia did not differ between the basal analogues, except for NPL which was associated with increased incidence compared with Deg‐100, detemir, Gla‐100, and Gla‐300.
Conclusions
Low‐quality, indirect evidence indicates that existing basal insulin analogues do not differ substantially in their glucose‐lowering efficacy in type 2 diabetes. Certain analogues may be associated with lower risk for nocturnal hypoglycemia (Deg‐100, Deg‐200, and Gla‐300) or less weight gain (detemir and Gla‐300).
The BRIGHT trial, the much awaited, first direct head‐to‐head comparison between the two second‐generation long‐acting insulin analogs, insulin glargine U300 (Toujeo) and insulin degludec (Tresiba), has now been published, showing essentially the same efficacy in terms of improvement in glycemic control and incidence of hypoglycemia between the two analogs in insulin‐naïve adults with type 2 diabetes. Similar findings were also demonstrated after initiating basal insulin therapy with either glargine U300 or degludec in insulin‐naïve subjects in the real‐world, observational study by Sullivan et al., whereas the comparable database analysis by Tribaldi et al. showed a small difference in HbA1c improvement and greater reductions in hypoglycemia incidence in favor of degludec. The latter data, however, have been criticized for inadequate matching between groups at baseline, which might have had a bearing on the results (2). In patients with type 2 diabetes switching to the two second‐generation analogs from other basal insulins, the presently referenced observational studies along with findings from an earlier data analysis (3) also suggest clinical effectiveness equivalence between glargine U300 and degludec. More evidence will hopefully be obtained from another head‐to‐head, randomized controlled trial, with the primary aim to compare the effect of glargine U300 versus degludec on severe or blood glucose (BG)–confirmed symptomatic hypoglycemia in subjects with type 2 diabetes on prior basal insulin therapy. Initially, the trial was planned for a treatment period of 52 weeks (16 weeks titration plus 36 weeks maintenance). However, due to reliability concerns regarding the glycemic data collection system used, the trial has been prolonged up to 88 weeks, together with replacement of the glucose meter and collection of self‐measured blood glucose and reported hypoglycemic episodes (4). While awaiting the final results of this trial, the existing data conceivably suggest no major differences in the clinical effectiveness of glargine U300 and degludec. Notably, the network analysis conducted by Madenidou and co‐workers suggested only minor differences in the glucose‐lowering effects of glargine U300 and degludec, respectively, versus other basal insulin analogs, whereas they were both associated with lower risk of nocturnal hypoglycemia. Hence, as has been suggested (5), second‐generation basal insulin analogs may be considered preferentially in selected patient groups with type 2 diabetes, and especially in those with recurrent hypoglycemic events including nocturnal episodes, in older subjects and those living alone, and in patients with other comorbidities rendering hypoglycemic events potentially dangerous. Moreover, as most data comparing glargine U300 and degludec have been derived from studies in type 2 diabetes, it is still unclear whether there are any clinically meaningful differences between the two in type 1 diabetes.
Oral Basal Insulin: Clinical Proof of Concept in Humans
The effect of food intake on the pharmacokinetics of oral basal insulin: a randomised crossover trial in healthy male subjects
Halberg IB1, Lyby K1, Wassermann K1, Heise T2, Plum‐Mörschel L3, Zijlstra E2
1Novo Nordisk A/S, Søborg, Denmark; 2Profil Institut für Stoffwechselforschung GmbH, Neuss, Germany; 3Profil Mainz GmbH, Mainz, Germany
Background
Insulin 338 (I338) is a novel tablet formulation of a long‐acting basal insulin for oral administration. The aim of this study was to investigate the effect of timing of food intake on single‐dose pharmacokinetics of I338 in healthy male adults.
Methods
A randomized, open‐label, four‐period, crossover trial, where the participants after an overnight fast were given single fixed doses of I338 0, 30, 60, or 360 minutes before consuming a standardized meal. Blood samples for pharmacokinetic measurements were taken up to 288 hours after oral I338 intake.
Results
Total exposure (area under the concentration time‐curve from time zero to infinity) and maximum concentration of I338 were both lower for 0 versus 360 minutes post‐dose fasting; the respective ratios were 0.36 ([95% CI 0.36–0.49], P<0.001) and 0.35 [95% CI 0.25–0.49], P<0.001). No statistically significant differences were found in total exposure and maximum concentration of I338 for 30 or 60 minutes versus 360 minutes post‐dose fasting (ratios 30 vs 360 minutes: 0.85 [95% CI 0.61–1.21], P=0.36, and 0.86 [95% CI 0.59–1.26], P=0.42, respectively, and ratios 60 versus 360 minutes: 0.96 [95% CI 0.72–1.28], P=0.77, and 0.99 [95% CI 0.75–1.31], P=0.95, respectively). The mean half‐life was approximately 55 hours, irrespective of the post‐dose fasting duration. No safety issues were registered during the study.
Conclusions
Oral I338 pharmacokinetics are not influenced by food intake from 30 minutes after dosing. Consequently, after morning oral administration of I338, breakfast may be consumed 30 minutes thereafter.
Efficacy and safety of oral basal insulin versus subcutaneous insulin glargine in type 2 diabetes: a randomised, double‐blind, phase 2 trial
Halberg IB1, Lyby K1, Wassermann K1, Heise T2, Zijlstra E2, and Plum‐Mörschel L3
1Novo Nordisk A/S, Søborg, Denmark; 2Profil Institut für Stoffwechselforschung GmbH, Neuss, Germany; 3Profil Mainz GmbH, Mainz, Germany
Background
In this phase 2 study, the efficacy and safety of the long‐acting, oral insulin 338 (I338) was assessed in insulin‐naïve adults with type 2 diabetes.
Methods
A randomized, double‐blind, double‐dummy, parallel trial was conducted for 8 weeks at two research centers. Fifty adults with type 2 diabetes inadequately controlled on metformin monotherapy or in combination with other oral glucose‐lowering drugs (HbA1c 7.0%–10.0%; BMI 25.0–40.0 kg/m2) were randomized (stratified by baseline therapies) to receive once‐daily I338 plus subcutaneous placebo (I338 group; n=25) or once‐daily insulin glargine 100 units/mL plus oral placebo (IGlar group; n=25). In both groups, medication was administered in the morning after an overnight fast. Participants and investigators were masked to treatment assignment. The recommended starting doses were 2,700 nmol I338 or 10 units IGlar. Weekly insulin dose titration was performed with the aim to achieve self‐measured fasting plasma glucose concentrations between 4.4 to 7.0 mmol/L. Maximum allowed doses of I338 and IGlar were 16 200 nmol and 60 units, respectively. Primary endpoint was change in fasting plasma glucose (FPG) at 8 weeks.
Results
Mean FPG at baseline was 9.7±2.8 (SD) mmol/L in the I338 group, and 9.1±1.7 mmol/L in the IGlar group. Least square mean FPG at 8 weeks was 7.1 mmol/L (95% CI 6.4–7.8) in the I338 group and 6.8 mmol/L (95% CI 6.5–7.1) in the IGlar group; the treatment difference being 0.3 mmol/L ([95% CI −0.5 to 1.1]; P=0.46). Incidence of adverse events were comparable for both treatments; most of which were mild and assessed unlikely to be related to the trial product. Incidence of hypoglycemia was low in both the I338 group (7 events) and IGlar group (11 events), and no severe hypoglycemic events were registered.
Conclusions
The findings suggest that treatment with an oral basal insulin is achievable and can safely improve glycemic control in insulin‐naïve adults with type 2 diabetes over 8 weeks, with an efficacy not different from that of a currently widely used basal insulin analog.
For a long time, the quest for oral insulin administration has been explored, but with little success (6 –8). Subcutaneously administered insulin is taken up by the peripheral circulation, whereas oral insulin can more closely mimic normal physiology by being absorbed from the gastrointestinal tract and via the portal vein be delivered directly to the liver. Challenges with oral delivery of insulin include local proteolytic degradation and restricted absorption across the intestinal epithelium, resulting in low bioavailability and therefore necessitating high doses of insulin to be administered. Low absorption rates also suggest that most insulin will remain in the gastrointestinal tract, which might imply safety concerns owing to its mitogenic effect. Furthermore, the absorption of oral insulin is influenced by food ingestion, leading to variability of pharmacokinetic and pharmacodynamic properties.
While most previous pharmacological developments of oral insulin have focused on short‐acting, mealtime insulin preparations, I338 has been developed by Novo Nordisk as a long‐acting basal insulin analog formulated in a film coated tablet with an absorption‐enhancer (sodium caprate). The insulin molecule has been modified with amino acid substitutions to make it less vulnerable for proteolytic degradation. Moreover, like with their other long‐acting insulin analogs detemir and degludec, I338 has been acetylated via a linker with an 18‐carbon fatty diacid, leading to reversible binding to albumin and protracted release.
In the first referenced article by Halberg and colleagues, it was ascertained that the pharmacokinetics of single doses of I338 (8,100 nmol) remained fairly the same if oral administration was given 30 minutes or more before food intake. Then, median onset of appearance was about 10 minutes, median maximum concentration 40–60 minutes postdosing, and the mean half‐life about 55 hours. In the clinical trial with I338, the starting dose was lower, but most participants were titrated to higher doses (6 out of 25 reaching the maximum allowed dose of 16,200 nmol at the end of the study period). Compared with end‐of‐trial glargine doses in the comparator group, the dose of I338 was about 58 times the dose of insulin glargine (i.e., bioavailability of I338 less than 2% of glargine). Nevertheless, given this difference in administered doses, the effectiveness of oral I338 on glucose control in adults with type 2 diabetes on prior oral antidiabetic drugs was comparable to that with the conventional basal insulin analog, albeit with somewhat higher glucose variability. As Mathieu commented (9), this is indeed a proof of concept for oral delivery of basal insulin. Disappointingly, however, further development of I338 in its present form has been terminated because of the low bioavailability, which would demand such a costly product that has been considered not commercially feasible. Yet, the saga of oral insulins will most probably be continued and will be followed in future Yearbooks.
Biosimilar Insulin
Looking toward the near future of biosimilar insulins (BioIns) in the United States, an open question is will the world will change drastically when insulins are regarded as biosimilars by the Food and Drug Administration (FDA) in March 2020? Until now, similar insulin products are approved in the United States by a 505(b)(2) abbreviated pathway by the FDA; in the future they will be regulated through the 351(k) pathway which was designed specifically for biosimilars. The FDA held a public hearing in May 2019 about the future of insulin biosimilars to discuss its regulatory process for biosimilar and interchangeable insulin products. We will have to see if any changes show up in the United States when this approval process for insulins will become active and what impact this will have on insulin prices (10,11).
A motivation for other insulin manufacturer to get their insulins approved as BioIns in the United States market is the good market success of the Eli Lilly/Boehringer Ingelheim insulin (Basaglar non‐European countries and Abasaglar in Europe) (12). However, it has not gained so much market uptake in the European Union (EU).
Other companies are developing BioIns and some have progressed considerably in the clinical development process; however, it is not clear when which of these BioIns will enter the crowded insulin market. It is of interest to note that companies not known to be active in this market try to change this by cooperating with other partners; for example, Novartis’ Sandoz division aims to commercialize BioIns (glargine, lispro, and aspart) from the Chinese insulin supplier Gan & Lee. It will remain to be seen how many insulin manufacturers can stay on this market if the insulin prices start to decline due to more competition. If a manufacturer does not sell a sufficient amount of insulin in a given time period, manufacturing of the insulin might become unprofitable. Such economic aspects appear also to be a major reason why the approved BioIns Lusduna was not brought to the market by Merck and Samsung. Another reason might also be a lawsuit against their insulin glargine by Sanofi. A year ago, Sanofi brought the first BioIns (Admelog) of a rapid‐acting insulin analog (insulin lispro) to the market; it appears as if this BioIns is doing well. One outcome of the ongoing and massive discussion about insulin prices in the United States is that Eli Lilly is now offering insulin lispro at half the price. That this, insulin is regarded as an “authorized generic” insulin by the FDA, which is an interesting shift in terminology. Subsequently, Lilly is now using this term in case of insulin which (with the exception of the brand name) is identical to the reference drug and is manufactured in the same facilities as Humalog. The reasons for bringing this insulin to the market have been criticized (13).
The only new BioIns that has entered the market in Europe (and also in Japan under a different name and in a different alliance) in the last year is another insulin glargine (Semglee). This was developed by the United States–based generics manufacturer Mylan in cooperation with the Indian pharmaceutical company BioCon. This BioIns is already on the market in Japan, South Korea, and the United Arab Emirates and was approved in the EU; however, recently it is only on the market in the United Kingdom. The plan is to launch this BioIns in the United States in 2020. One reason for this delay is probably the lawsuit Sanofi has filed against Mylan in the United States alleging infringement of its patents. It is of interest to note that the initial application of Mylan was rejected by the FDA; that is, they (and BioCon) received a “complete response letter” listing a number of quality issues that inspectors have found in the manufacturing plant. BioCon appears to have solved these issues later in 2018. Mylan is seeking an interchangeability designation. Interchangeability means the practice of changing one insulin for another that is expected to achieve the same blood glucose lowering effect in any patient with diabetes on the initiative or with the agreement of the physician. This requires that the insulin can be regarded as interchangeable from a regulatory point of view. The FDA has now described in more detail what their expectations are for such a label; however, as until now none of the insulins in the United States could be approved as a BioIns, none has received such a label. However, at the above‐mentioned FDA meeting in May 2019 the relevant aspects for an interchangeable label were discussed in detail. In a real‐life clinical study performed in China, injection of the branded insulin glargine, Lantus, provided better fasting glycemic control compared with the biosimilar insulin glargine, Basalin, without increased hypoglycemia risk at a similar insulin dose (14). It has to be mentioned that Basalin was not approved as a BioIns in any of the regulated markets. In a similarly designed Japanese study with Abasaglar, no differences in HbA1c values between patients treated with the originator insulin glargine and the BioIns were observed; however, fasting glycemic values were not reported (15). Also, there are good reasons why the regulatory authorities in the United States and the EU require more precise measures than HbA1c results from clinical trials to approve an insulin as a BioIns.
In the last year, very few clinical studies (or other papers) dealing with BioIns were published; however, these two report clinical data obtained with Semglee in patients with type 1 or type 2 diabetes (16,17). Despite the fact that BioIns are now on the market for some years, these are still early days for them.
Efficacy and safety of MYL‐1501D vs insulin glargine in patients with type 1 diabetes after 52 weeks: results of the INSTRIDE 1 phase III study
Blevins TC1, Barve A2, Sun B2, Ankersen M2
1Texas Diabetes and Endocrinology, Austin, TX; 2Mylan Inc., Canonsburg, PA
Background
The safety and efficacy of a proposed insulin glargine biosimilar, MYL‐1501D, was evaluated in subjects with type 1 diabetes mellitus (T1DM).
Methods
INSTRIDE 1, a 52‐week, open‐label, randomized, phase 3 study in patients with T1DM, investigated the safety and efficacy of MYL‐1501D and reference insulin glargine to determine whether once‐daily MYL‐1501D was noninferior to once‐daily insulin glargine when administered in tandem with mealtime insulin lispro based on change in HbA1c from baseline to week 24. Changes in fasting plasma glucose, insulin dose, self‐monitored blood glucose, and immunogenicity from baseline, and occurrences of hypoglycemic, nocturnal hypoglycemic, and adverse events up to week 52 were secondary endpoints of the study.
Results
Study participants (n=588) were randomized 1:1 into two groups, MYL‐1501D or reference insulin glargine in combination with thrice‐daily mealtime insulin lispro. From baseline to week 24, the mean change in HbA1c was 0.14% (SE 0.054; [95% confidence interval 0.033, 0.244]) for MYL‐1501D and 0.11% (SE 0.054 [95% CI 0.007, 0.220]) for reference insulin glargine. The safety profile of MYL‐1501D was similar to that of reference insulin glargine, and MYL‐1501D was well tolerated in study patients through week 52.
Conclusions
MYL‐1501D was found noninferior to reference insulin glargine based on the upper 95% CI limit for mean change in HbA1c. No clinically meaningful differences between groups were found with respect to incidence of overall and nocturnal hypoglycemia, local or systemic reactions, safety, or immunogenicity.
Efficacy and safety of MYL‐1501D vs insulin glargine in patients with type 2 diabetes after 24 weeks: Results of the phase III INSTRIDE 2 study
Blevins TC1, Barve A2, Sun B2, Raiter Y3, Aubonnet P4, Muniz R2, Athalye S5, Ankersen M2
1Texas Diabetes and Endocrinology, Austin, TX; 2Mylan Inc., Canonsburg, PA, 3Mylan EPD, Amstelveen, The Netherlands; 4Mylan EPD, Allschwil, Switzerland; 5Biocon Research Ltd, Bangalore, India
Background
MYL‐1501D is a proposed biosimilar or follow‐on biological agent to marketed insulin glargine. In the phase 3 INSTRIDE 2 study, change in HbA1c level was used to evaluate the noninferiority of MYL‐1501D to reference insulin glargine was assessed.
Methods
Insulin‐naïve and insulin‐non‐naïve patients with type 2 diabetes mellitus who were receiving oral antidiabetic drugs were included in the INSTRIDE 2 study comparing the efficacy and safety of MYL‐1501D with those of reference insulin glargine. The primary efficacy endpoint of this multicenter, open‐label, randomized, parallel‐group, phase 3 noninferiority study was change in HbA1c from baseline to week 24. Metabolic readouts (e.g., changes in insulin dosage, fasting plasma glucose, self‐monitored blood glucose), immunogenicity and adverse events, including hypoglycemia, and nighttime hypoglycemic events were secondary endpoints.
Results
A total of 560 patients were randomized to MYL‐1501D or insulin glargine in combination with oral antidiabetic drugs for the 24‐week trial. Mean change in HbA1c from baseline to week 24 for MYL‐1501D was −0.60% (95% CI −0.78, −0.41) and, for reference insulin glargine, it was −0.66% (95% CI −0.84, −0.48). MYL‐1501D was well tolerated by study participants, with a safety profile similar to that of reference insulin glargine.
Conclusions
MYL‐1501D was shown to be noninferior to reference insulin glargine for reduction of HbA1c during the 24 weeks of treatment. Secondary endpoints, including hypoglycemia and nocturnal hypoglycemia, local and systemic reactions, other safety variables, and immunogenicity, were found to be similar between the two groups.
These two multicenter, open‐label, randomized, parallel‐group, phase 3 studies in patients with type 1 or type 2 diabetes with Semglee over half a year or a full year showed no clinical relevant differences in a number of outcome parameters between this BioIns and the originator insulin glargine.
The Early Days of Smart Insulins
Glucose transporter inhibitor‐conjugated insulin mitigates hypoglycemia
Wang J1,2, Yu J3, Zhang Y3, Kahkoska AR4, Wang Z1,2, Fang J1, Whitelegge JP5, Li S1,6, Buse JB4, Gu Z2,7,8,9
1Department of Bioengineering, University of California, Los Angeles, CA; 2California NanoSystems Institute, University of California, Los Angeles, CA; 3Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC; 4Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC; 5The Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA; 6Department of Medicine, University of California, Los Angeles, CA; 7Department of Bioengineering, University of California, Los Angeles, CA; 8Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA; 9Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA
Abstract
Insulin therapy in patients of type 1 and advanced type 2 diabetes carries with it an increased risk of potentially fatal hypoglycemia. This complication could be mitigated by a glucose‐responsive insulin analog. Here we describe an insulin‐facilitated glucose transporter (Glut) inhibitor conjugate—a long‐acting insulin analog that can establish an endogenous Glut‐associated delivery reservoir of insulin that is capable of modulating glucose metabolism in a blood glucose–dependent manner. The binding affinity of this insulin analog to endogenous Glut is modulated by plasma and tissue glucose levels. In conditions of hyperglycemia (e.g., uncontrolled diabetes or the postprandial state), the in situ–generated insulin analog–Glut complex dissociates, freeing the insulin analog and glucose‐accessible Glut to restore normal blood glucose levels. If a patient receives too much insulin, enhanced binding of insulin analog to Glut suppresses the glucose transport activity of Glut, further reducing uptake of glucose. A type 1 diabetic mouse model was used to demonstrate the ability of this insulin conjugate to regulate blood glucose levels within a normal range, decreasing the risk of hypoglycemia.
Glucose‐responsive “smart” insulins, if realized, would be one of the most exciting advances in diabetes care. In 2019 a team of bioengineers at the University of California, Los Angeles, has developed a form of smart insulin, dubbed i‐insulin, which comprises an insulin analog attached to a glucose transporter inhibitor. This acts to prevent over‐uptake of glucose into cells if blood glucose levels drop. When tested in diabetic mice the modified insulin kept blood glucose levels within the normal range longer and protected the animals from becoming hypoglycemic even when an extra dose of the i‐insulin was administered. As we mention every year, considerable work is needed before human studies with this approach are attempted.
Ultra‐Rapid Insulins: Improving Meal‐Time Glucose Levels
Greater early postprandial suppression of endogenous glucose production and higher initial glucose disappearance is achieved with fast‐acting insulin aspart compared with insulin aspart
Basu A1, Pieber TR2, Hansen AK3, Sach‐Friedl S2, Erichsen L3, Basu R1, Haahr H3
1Division of Endocrinology, University of Virginia, Charlottesville, VA; 2Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; 3Novo Nordisk, Søborg, Denmark
Aims
The mechanisms by which fast‐acting insulin aspart (faster aspart) achieved lower postprandial glucose (PPG) concentrations versus insulin aspart (IAsp) were investigated.
Material and Methods
A randomized, double‐blind, crossover trial was carried out in 41 patients with type 1 diabetes. Each patient received subcutaneous single doses of faster aspart and IAsp (individualized for each participant) coupled with a standardized mixed meal that included 75 g of (1‐13C) glucose–labeled carbohydrates. The triple‐tracer meal method using continuous, variable (6‐3H) glucose and (6,6‐2H2) glucose infusion was used to ascertain PPG turnover.
Results
Faster aspart resulted in 32% greater insulin exposure within the first hour than did IAsp. The treatment ratio for faster aspart/IAsp was 1.32 ([95% confidence interval (CI) 1.18, 1.48]; P<0.001), which led to a nonsignificantly smaller 0.59‐mmol/L PPG increment at 1 hour (ΔPG1h; treatment difference faster aspart–IAsp −0.59 mmol/L [95% CI −1.19, 0.01]; P=0.055). The trend toward reduced ΔPG1h with faster aspart was attributable to 12% greater suppression of endogenous glucose production (treatment ratio 1.12 [95% CI 1.01, 1.25]; P=0.040) and 23% higher glucose disappearance (1.23 [95% CI 1.05, 1.45]; P=0.012) with faster aspart than with IAsp during the first hour. Faster aspart produced 36% greater suppression of free fatty acid levels during the first hour than that recorded for IAsp (1.36 [95% CI 1.01, 1.88]; P=0.042).
Conclusions
Compared with IAsp, faster aspart led to a higher rate of glucose disappearance as well as greater suppression of EGP, resulting in the trend toward improved PPG control with faster aspart.
Fast‐acting insulin aspart versus insulin aspart in the setting of insulin degludec‐treated type 1 diabetes: efficacy and safety from a randomized double‐blind trial
Buse JB1, Carlson AL2, Komatsu M3, Mosenzon O4, Rose L5, Liang B6, Buchholtz K6, Horio H7, Kadowaki T8
1Division of Endocrinology, Department of Medicine, University of North Carolina School of Medicine, NC; 2International Diabetes Center, Minneapolis, MN; 3Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Shinshu University School of Medicine, Nagano, Japan; 4Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel; 5Institute of Diabetes Research, Münster, Germany; 6Novo Nordisk A/S, Søborg, Denmark; 7Novo Nordisk Pharma Ltd, Tokyo, Japan; 8Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Aims
This phase 3b, multicenter, treat‐to‐target trial (Clinical trial registry NCT02500706, ClinicalTrials.gov, onset 8) was carried out in adult patients with type 1 diabetes (T1D) to evaluate the efficacy and safety of mealtime or postprandial fast‐acting insulin aspart (faster aspart) versus mealtime insulin aspart (IAsp), both in combination with insulin degludec.
Methods
The study was carried out at 146 centers in 12 countries/regions. Participants were randomized to double‐blind mealtime faster aspart (n=342) or IAsp (n=342) or open‐label postmeal faster aspart (n=341). The primary endpoint was change in HbA1c from baseline after 26 weeks of treatment. All available information, regardless of treatment discontinuation, was used in our evaluation.
Results
Of 1025 participants, 1007 participants (98.2%) completed the trial, and 999 (97.5%) of these, similarly distributed across treatment arms, completed the full 26‐week treatment period without early discontinuation of their randomly assigned treatment. Noninferiority for the change in HbA1c from baseline was confirmed for mealtime and postmeal faster aspart versus IAsp (estimated treatment difference [ETD] −0.02% [95% CI −0.11, 0.07] and 0.10% [0.004, 0.19] respectively). Mealtime faster aspart was found to be superior to IAsp for 1‐hour PPG increment using a meal test (ETD, −0.90 mmol/L [ −1.36; −0.45]; P<0.001). Self‐monitored 1‐hour PPG increment favored faster aspart at breakfast (ETD, −0.58 mmol/L [ −0.99; −0.17]; P=0.006) and across all meals (−0.48 mmol/L [ −0.74; −0.21]; P<0.001). Both safety profiles and overall rate of severe or blood glucose‐confirmed hypoglycemia were similar between the two treatments; however, significantly less hypoglycemia was observed 3–4 hours after meals with mealtime faster aspart.
Conclusions
Both mealtime and postmeal faster aspart in conjunction with insulin degludec provided effective glycemic control compared with IAsp, and neither exhibited increased safety risk. Mealtime faster aspart provided better control of PPG control compared with that of IAsp.
A randomized, multicentre trial evaluating the efficacy and safety of fast‐acting insulin aspart in continuous subcutaneous insulin infusion in adults with type 1 diabetes (onset 5)
Klonoff DC1, Evans ML2, Lane W3, Kempe HP4, Renard E5, DeVries JH6,7, Graungaard T8, Hyseni A9, Gondolf T9, Battelino T10
1Diabetes Research Institute, Mills‐Peninsula Medical Center, San Mateo, CA; 2Wellcome Trust/MRC Institute of Metabolic Science and Department of Medicine, University of Cambridge, Cambridge, UK; 3Mountain Diabetes and Endocrine Center, Asheville, NC; 4Centre for Diabetes and Nutrition Ludwigshafen, Ludwigshafen, Germany;5 Department of Endocrinology, Diabetes, and Nutrition and Clinical Investigation Centre, Montpellier University Hospital, Institute of Functional Genomics, CNRS, INSERM, University of Montpellier, Montpellier, France; 6Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 7Profil Institute of Metabolic Research, Neuss, Germany; 8Novo Nordisk A/S, Aalborg, Denmark; 9Novo Nordisk A/S, Søborg, Denmark; 10Department of Endocrinology, Diabetes and Metabolic Diseases, University Children's Hospital Ljubljana, and Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
This manuscript is also discussed in the article on Insulin Pumps, page S‐17.
Background
This onset 5 study was designed to evaluate the efficacy and safety of fast‐acting insulin aspart (faster aspart) versus IAsp used in continuous subcutaneous insulin infusion (CSII) was evaluated in adults with T1D.
Materials and Methods
A double‐blind, treat‐to‐target, randomized, 16‐week trial was conducted at 92 sites in nine countries (Belgium, Canada, France, Germany, the Netherlands, Russian Federation, Slovenia, the UK, and the United States) to investigate CSII treatment with faster aspart (n=236) or IAsp (n=236). Participants were adults (≥18 years) with T1D (diagnosed clinically for ≥12 months) who had been using the same insulin pump (MiniMed530G, Paradigm Veo, Paradigm Revel, or Paradigm; Medtronic Inc, Minneapolis, Minnesota) for CSII therapy with a rapid‐acting insulin analogue for ≥6 months prior to screening and were willing to continue using the same model throughout the study. The primary endpoint was change in HbA1c from baseline to the end of the trial (16 weeks). All available information, regardless of treatment discontinuation, was used for the evaluation of effect.
Results
A total of 463 participants (98.1%) completed the trial, 455 (96.4%) of whom completed the treatment period without prematurely discontinuing their randomized assigned treatment. Faster aspart was found noninferior to IAsp regarding the change from baseline in HbA1c. Mean HbA1c decreased from 58.4 mmol/mol (7.5%) at baseline to 57.8 mmol/mol (7.4%) with faster aspart and to 56.8 mmol/mol (7.4%) with IAsp at 16 weeks, with an ETD of 1.0 mmol/mol ([95% CI 0.14, 1.87] or 0.09% [95% CI 0.01, 0.17]; P<0.001) for noninferiority (0.4% margin; P<0.02 for statistical significance in favor of IAsp). Treatment with faster aspart produced superior change from baseline in 1‐hour PPG increment after a meal test that did IAsp (ETD −0.91 mmol/L [95% CI −1.43, −0.39] or −16.4 mg/dL [95% CI −25.7, −7.0]; P=0.001); statistically significant reductions were also measured at 30 minutes and 2 hours. This improvement in PPG was reflected in the change from baseline in 1‐hour interstitial glucose increment after all meals (ETD −0.21 mmol/L [95% CI −0.31, −0.11] or −3.77 mg/dL [95% CI −5.53, −2.01]). There was no statistically significant difference in the overall rate of treatment‐emergent severe or BG‐confirmed hypoglycemia between treatments (estimated rate ratio 1.00 [95% CI 0.85, 1.16]). A numerical imbalance in the number of severe hypoglycemic episodes between faster aspart and IAsp was noted in the 16‐week treatment period (21 vs 7) and in the 4‐week run‐in period (4 vs 0).
Conclusions
The results of this trial show that faster aspart provides an effective and safe option for CSII treatment in adults with T1D.
Efficacy and safety of fast‐acting insulin aspart compared with insulin aspart, both in combination with insulin degludec, in children and adolescents with type 1 diabetes: the onset 7 trial
Bode BW1, Iotova V2, Kovarenko M3, Laffel LM4, Rao PV5, Deenadayalan S6, Ekelund M6, Larsen SF6, Danne T7
1Atlanta Diabetes Associates, Atlanta, GA; 2University Hospital St. Marina, Medical University Varna, Varna, Bulgaria; 3Pediatric Department, Novosibirsk State Medical University of the Ministry of Health of the Russian Federation, Novosibirsk, Russia; 4Joslin Diabetes Center, Harvard Medical School, Boston, MA; 5Diabetes Research Society, Hyderabad, India; 6Novo Nordisk A/S, Søborg, Denmark; 7Children's Hospital Auf der Bult, Hannover, Germany.
Objective
A 26‐week, double‐blind, multicenter, onset 7 trial was conducted to confirm the efficacy and safety of faster aspart versus IAsp, both with basal insulin degludec, in pediatric patients with T1D.
Research Design and Methods
After a 12‐week run‐in, pediatric participants (1 to <18 years) with T1D were randomized to mealtime faster aspart (n=260), mealtime IAsp (n=258), or open‐label postmeal faster aspart (n=259). Change from baseline in HbA1c after 26 weeks of treatment was the primary endpoint, and treatment effect was evaluated using all available information without regard to discontinuation of treatment.
Results
Mealtime and postmeal faster aspart at week 26 were both noninferior to IAsp with respect to change from baseline in HbA1c (P<0.001 for noninferiority [0.4% margin]); the difference in favor of mealtime faster aspart was statistically different (estimated treatment difference −0.17% [95% CI −0.30; −0.03], −1.82 mmol/mol [ −3.28; −0.36]; P=0.014). The change from baseline in 1‐hour postprandial glucose level significantly favored mealtime faster aspart versus IAsp at breakfast, main evening meal, and across all meals (P<0.01 for all). Overall rates of severe or blood glucose‐confirmed hypoglycemia were not statistically significant. Mean total daily insulin dose was 0.92 units/kg for mealtime faster aspart, 0.92 units/kg for postmeal faster aspart, and 0.88 units/kg for mealtime IAsp.
Conclusions
Mealtime and postmeal faster aspart with insulin degludec was effective in controlling blood glucose without additional safety risks versus IAsp in pediatric patients with T1D. Mealtime faster aspart provided more effective HbA1c control than did IAsp.
Fast‐acting insulin aspart in people with type 2 diabetes: earlier onset and greater initial exposure and glucose‐lowering effect compared with insulin aspart
Pieber TR1, Svehlikova E1, Brunner M2, Halberg IB3, Due Thomsen KM4, Haahr H3
1Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; 2CF Clinical Research Center, Center for Medical Research, Medical University of Graz, Graz, Austria; 3Novo Nordisk, Søborg, Denmark; 4Novo Nordisk, Aalborg, Denmark
Background
A randomized, double‐blind, crossover study was conducted to examine the pharmacokinetic/pharmacodynamic properties of faster aspart versus IAsp were examined in patients with type 2 diabetes (T2D).
Materials and Methods
Sixty‐one people with T2D usually treated with insulin with or without oral antidiabetic drug(s) were included in the study. Each participant received single‐dose faster aspart and IAsp (0.3 U/kg) on separate visits, and blood samples were collected frequently until 12 hours after the dose was administered. Pharmacokinetic assessment was carried out on participant blood samples, and glucose‐lowering effect measured using a euglycemic clamp lasting up to 12 hours post‐dose (target 5.0 mmol/L).
Results
For faster aspart versus IAsp, both the serum IAsp pharmacokinetic profile and glucose‐lowering effect profile shifted to the left. Least squares mean (± SE) onset of appearance was 3.3±0.3 minutes for faster aspart, 1.2 minutes earlier than for IAsp ([95% CI −1.8, −0.5]; P=0.001). Onset of action for faster aspart was found to be 8.9 minutes earlier ([95% CI −12.1, −5.7]; P<0.001) than onset of action for IAsp. During the first half‐hour after dosing, treatment with faster aspart resulted in 89% larger IAsp exposure (ratio faster aspart/IAsp 1.89 [95% CI 1.56, 2.28]; P<.001) and 147% greater glucose‐lowering effect (2.47 [95% CI 1.58, 6.22]; P<0.001) than IAsp. Offset of exposure (time to 50% of maximum IAsp concentration in the late part of the pharmacokinetic profile) occurred earlier for faster aspart (difference faster aspart − IAsp −36.4 minutes [95% CI −55.3,−17.6]; P<0.001). For faster aspart − IAsp, the treatment difference in offset of glucose‐lowering effect (time to 50% of maximum glucose infusion rate in the late part of the glucose infusion rate profile) was −14.4 minutes ([95% CI −34.4,5.5]; P=0.152).
Conclusions
Previous studies have found faster aspart to be associated with earlier onset and greater initial exposure and glucose‐lowering effect compared with IAsp, in people with type 1 diabetes. This study confirms these results in people with T2D as well.
Ultra‐rapid BioChaperone lispro improves postprandial blood glucose excursions vs insulin lispro in a 14‐day crossover treatment study in people with type 1 diabetes
Andersen G1, Meiffren G2, Lamers D1, DeVries JH1, Ranson A2, Seroussi C2, Alluis B2, Gaudier M2, Soula O2, Heise T1
1Profil, Neuss, Germany; 2Adocia, Lyon, France
Background
BioChaperone Lispro (BCLIS) is an ultra‐rapid insulin lispro (LIS) formulation designed to accelerate the absorption of insulin lispro after subcutaneous administration. This trial was carried out to investigate the safety and efficacy BCLIS in adults with type 1 diabetes.
Materials and Methods
A randomized double‐blind study was conducted in 36 adult men (n=25) and women (n=11) with type 1 diabetes. Participants self‐administered individualized bolus doses of BCLIS or LIS during two 14‐day periods in a crossover fashion. Each participant was served an individualized solid mixed meal test (MMT) consisting of 50% carbohydrate, 29% fat, and 21% protein. Postprandial blood glucose (BG) was assessed after the MMTs, with additional randomization for the sequence of timing of insulin administration, immediately (t0), 15 minutes before (t−15), and 15 minutes after (t+15) meal start on days 1, 2, and 3, and with t0 administration on day 14. Pharmacokinetic (PK) variables were assessed on the two days with t0 MMTs. Participants also used individualized BCLIS or LIS for doses self‐injected immediately before meals during the two outpatient periods (day 3 to day 13) with an unchanged regimen of basal insulin.
Results
A total of 35 participants completed both treatment periods. The higher early postprandial PK exposure of BCLIS for MMTs with t0 administration led to significantly (30% to 40%) reduced 1‐ to 2‐hour postprandial BG excursions versus LIS, and the accelerated absorption and action of BCLIS lasted over 14 days; however, no difference in glucose excursion was observed over the full 360‐minute postprandial period. Postprandial BG control was similar for BCLIS injected at t+15 and LIS injected at t0. Safety and tolerability for BCLIS was similar to that of LIS. No injection site reactions were reported with BCLIS.
Conclusions
BCLIS was well tolerated and safe over 14 days of treatment and significantly improved postprandial BG versus LIS when administered at mealtime.
Better glycemic control with BioChaperone glargine lispro co‐formulation than with insulin lispro Mix25 or separate glargine and lispro administrations after a test meal in people with type 2 diabetes
Meiffren G1, Herbrand T2, Anastassiadis E3, Klein O2, DeVries JH2, Heise T2, Alluis B1, Mégret C1, Gaudier M1, Soula O1, Plum‐Mörschel L3
1Adocia, Lyon, France; 2Profil, Neuss, Germany; 3Profil, Mainz, Germany
Background
Because of its physico‐chemical properties, insulin glargine cannot typically be mixed with rapid‐acting insulins. BioChaperone BC147 is a polyanionic amphiphilic polymer that solubilizes insulin glargine at neutral pH, allowing glargine to form a stable formulation with fast‐acting insulin lispro (BioChaperone glargine lispro co‐formulation, or BC Combo).
Methods
A randomized, double‐blind, double‐dummy crossover study was carried out in 39 adults with T2DM (mean±SD age and glycated hemoglobin 60.8±7.5 years and 64±6 mmol/mol respectively) to investigate PK endpoints and PPG control after administration of BC Combo (75% insulin glargine, 25% insulin lispro), insulin lispro Mix25 (LMix), and separate injections of insulins glargine (75% total dose) and lispro (25% total dose [G + L]) immediately before ingestion of a mixed meal. Subjects received individualized bolus doses (mean 0.62 U/kg) of BC Combo, LMix, or G+L together with a 610‐kcal solid mixed meal (50% carbohydrate, 30% fat, 20% protein). Consistent insulin dosages were maintained for each study day. BC Combo improved early PPG control compared with LMix (incremental area under the blood glucose concentration‐time curve from 0 to 2 hours after the meal [ΔAUCBG,0–2h] reduction of 18%; P=0.0009) and G+L (ΔAUCBG,0–2h reduction of 10%; P=0.0450). A reduction in the per‐participant number of mealtime hypoglycemic episodes was observed with BC Combo (22 episodes in 14 participants) compared with LMix (43 episodes in 20 participants; P=0.0028), but the difference was not significantly different compared with G+L (28 episodes in 19 participants; P=0.2523). Patients experienced superior early PPG control with fewer hypoglycemic episodes while using BC Combo versus LMix as well as superior early PPG control compared with separate G+L administrations.
BioChaperone Lispro versus faster aspart and insulin aspart in patients with type 1 diabetes using continuous subcutaneous insulin infusion: A randomized euglycemic clamp study
Heise T1, Meiffren G2, Alluis B2, Seroussi C2, Ranson A2, Arrubla J1, Correia J2, Gaudier M2, Soula O2, Soula R2, DeVries JH1, Klein O1, Bode B3
1Profil, Neuss, Germany; 2Adocia, Lyon, France; 3Atlanta Diabetes Associates, Atlanta, GA
Abstract
A randomized, double‐blind, three‐way crossover glucose clamp study was carried out to examine the pharmacodynamics (PD) and pharmacokinetics (PK) of BCLIS, faster insulin aspart (FIAsp), and insulin aspart (IAsp) in 43 patients with T1D using an insulin pump. The primary endpoint of the study was area under the glucose infusion rate curve (AUCGIR) at 0–60 minutes. Participants received a bolus dose of each insulin (0.15 U/kg) in addition to a basal rate (0.01 U/kg/h) delivered via insulin pump. With BCLIS, AUCGIR, 0–60 minutes was improved compared with IAsp (least square means ratio, 1.63 [95% CI 1.44–1.88]; P<0.0001) and was similar to FIAsp (least square means ratio, 1.06 [95% CI 0.94–1.18]; P=0.4609). BCLIS showed faster‐on PD than IAsp and faster‐off PD than either FIAsp or IAsp. Early exposure (AUCins, 0–60 minutes) was significantly higher and late exposure (AUCins, 120–600 minutes) was lower with BCLIS than with either of the other insulins. In patients with T1D using an insulin pump, BCLIS more closely mimics secretion and action of prandial insulin than does IAsp. BCLIS also shows a faster off‐PD than does FIAsp.
Despite the introduction of faster aspart on the market more than a year ago, there is still controversy regarding the clinical impact of this new formulation. The faster profile is mediated through niacinamide, which accelerates the initial insulin aspart absorption, but the mechanism of action appears to be multifaceted. Niacinamide increases the initial abundance of insulin aspart monomers and transport of insulin aspart after subcutaneous administration and also mediates a transient, local vasodilatory effect (18). Surprisingly, the pediatric data of onset®7 showed a better effect on HbA1c for the combination of the ultra‐rapid insulin with the ultra‐long basal insulin degludec compared with adult onset®8 study with identical design. However, the improved postprandial continuous glucose monitoring (CGM) curves in both trials are virtually superimposable. Not surprisingly, faster aspart is particularly effective when used in patients adjusting their prandial insulin according to carb counting (19). In contrast, the HbA1c levels were higher with faster aspart when used in the pump. Evaluation of CGM profiles indicated that there was no difference between the two study groups during the day, but nocturnal values in the faster aspart treatment group were higher compared with conventional insulin aspart and this might have influenced HbA1c. Overall, it can be deduced from these profiles that optimizing the basal rate according to the respective pharmacokinetic profile of the meal insulin might have been useful in both study arms. The use of a split‐ or multiwave bolus for high‐protein and high‐fat dinners can further optimize the glucose levels. As the CGM readings were blinded, the participants could not use this data to optimize their pump setting. A personal CGM device was used only in 25% of the participants. Thus, due to the faster and shorter profile of action of faster aspart, adjustments in basal rate and meal boluses should be made to increase the potential benefit of faster aspart for people with diabetes (20). Studies using this insulin in a hybrid‐closed loop system with automatic adjustment of the basal rate are underway. Data presented so far indicate that the other ultra‐rapid insulins BioChaperone lispro and trepostinil lispro are differing slightly from faster aspart in the pharmacokinetic and pharmacodynamic profile and in case of BioChaperone Lispo regarding the co‐formulation with long‐acting insulins. It still remains to be seen whether these insulins will gain a widespread clinical use in type 1 diabetes and for selected patients with type 2 diabetes.
Footnotes
Author Disclosure Statement
L.H. is a consultant for a number of insulin manufacturing companies. J.B. has received honoraria for consulting and/or lecture fees from Abbott Diabetes Care, AstraZeneca, and Novo Nordisk. T.D. has received research support or has consulted for AstraZeneca, Boehringer, Dexcom, Insulet, Eli Lilly, Medtronic, Novo Nordisk, Roche, and is a shareholder of DreaMed-Diabetes Ltd.