Differentiating Basal Insulin Preparations: Understanding How They Work Explains Why They Are Different
Since the introduction of insulin as a life-saving agent for patients with type 1 diabetes, insulin preparations have evolved to approximate physiologic insulin delivery profiles to meet prandial and basal insulin needs. While prandial insulins are designed to have quick time–action profiles that minimize postprandial glucose excursions, basal insulins are designed to have a protracted time–action profile to facilitate basal glucose control over 24 h. Given that all insulins have the same mechanism of action at the target tissue level, the differences in time–action profiles are achieved through different mechanisms of protraction, resulting in different behaviors in the subcutaneous space and different rates of absorption into the circulation. Herein, we evaluate the differences in basal insulin preparations based on their differential mechanisms of protraction, and the resulting clinical action profiles. Multiple randomized control trials and real-world evidence studies have demonstrated that the newer second-generation basal insulin analogs, insulin glargine 300 units/mL and insulin degludec 100 or 200 units/mL, provide stable glycemic control with once-daily dosing and are associated with a reduced risk of hypoglycemia compared with previous-generation basal insulin analogs insulin glargine 100 units/mL and insulin detemir. These advantages can lead to decreased healthcare resource utilization and cost. With this collective knowledge, healthcare providers and payers can make educated and well-informed decisions when determining which treatment regimen best meets the needs of each individual patient.
Funding: Sanofi US, Inc.
KeywordsBasal insulin Hypoglycemia Pharmacodynamics Pharmacokinetics Protraction Second-generation long-acting insulin
Since the introduction of insulin as a life-saving drug for patients with type 1 diabetes (T1D) in 1922, insulin preparations have evolved to develop improved prandial and basal insulins to mimic pancreatic insulin secretion profiles. Under normal physiologic conditions, the secretion of insulin by pancreatic β-cells is a dynamic process that quickly responds to the changing needs of glycemic control of the individual throughout the day and night. In addition to maintaining fairly constant basal levels of insulin secretion during periods of fasting, the pancreas must also be capable of storing and releasing a surge of insulin to prevent rapid postprandial peaks in blood glucose levels. To artificially mimic this sophisticated pattern of insulin production and secretion, different formulations of exogenous insulin with complementary time–action profiles are required.
Basal Insulins: Mechanisms of Protraction
Mechanism of protraction
Short-acting regular insulin
Nil (animal and recombinant human forms)
Intermediate-acting NPH insulin
Nil (animal and recombinant human forms)
Preformed precipitate of protamine–insulin conglomerates the crystals of which are retained in “heaps” at injection depot
ProB28 → Lys
LysB29 → Pro
More rapid circulation/action than regular human insulin
ProB28 → Asp
More rapid circulation/action than regular human insulin
AsnB3 → Lys
LysB29 → Glu
More rapid circulation/action than regular human insulin
AspA21 → Gly
Soluble in acidic pH pre-injection. Forms microprecipitates while equilibrating with physiologic pH at the injection site; free glargine then dissociates from the injection depot and is absorbed into the circulation
Modification of LysB29 by a tethered fatty acid
Self-association at the injection depot as dihexamers and reversible binding, via fatty acid linker, to albumin at the injection depot and in the circulation
AspA21 → Gly
Soluble in acidic pH pre-injection. Precipitates at physiologic pH, but with more compact microprecipitates compared with Gla-100, resulting in a reduced surface area from which more protracted absorption can occur
Modification of LysB29 by a dicarboxylic acid
Addition of a fatty acid side chain
Multihexamer chain formation at the injection depot, with dissociation of zinc allowing hexamer breakdown as well as binding to serum albumin via attached fatty acid linker
Human Basal Insulin: NPH Insulin
NPH insulin, introduced in the 1940s, was one of the first intermediate-acting insulin formulations . The addition of protamine results in a protamine–insulin complex that precipitates in solution before injection. After injection, the protamine–insulin complex diffuses slowly from the subcutaneous space, resulting in an intermediate-acting time–action profile .
First-Generation Basal Insulin Analogs: Insulin Glargine 100 Units/mL and Insulin Detemir
The first-generation basal insulin analogs were developed using recombinant deoxyribonucleic acid technology to alter the amino acid sequence of human insulin to create the desired effects. The first of these basal insulin analogs, insulin glargine 100 units/mL (Gla-100) became available in the year 2000 and was soon followed by insulin detemir (IDet) in 2005 . In the case of Gla-100, the A21-asparagine of human insulin is replaced by glycine, and two arginine residues are added to B30. These modifications increase the isoelectric point of the insulin analog, making it soluble in acidic conditions (before injection), but when exposed to the higher (physiologic) pH of the human subcutaneous space after injection, microprecipitates form in the injection depot [3, 4]. Monomeric Gla-100 is then slowly released into the circulation from the microprecipitate of the injection depot (a process that depends on the surface area of the injection depot), thereby protracting the PK profile of insulin glargine . In the case of IDet, the amino acid sequence of the human insulin is altered and a 14-carbon myristoyl fatty acid is added to the B29-lysine residue. This results in a soluble insulin that self-associates into dihexamers in the subcutaneous space and reversibly binds to albumin via the fatty acid linker, allowing for slower release of monomeric free insulin .
Second-Generation Basal Insulin Analogs: Insulin Glargine 300 Units/mL and Insulin Degludec 100 Units/mL and 200 Units/mL
Although the first-generation basal insulin analogs represented a significant advance in basal insulin technology, allowing for less hypoglycemia compared with NPH insulin, there was still residual hypoglycemia risk, and further improvements in the time–action profile were needed. The second-generation basal insulin analogs insulin glargine 300 units/mL (Gla-300) and insulin degludec (IDeg) were introduced in 2015.
The act of concentrating insulin and reducing injection volume does not automatically alter the time–action profile. An understanding of the mechanism of protraction is important to explain this. In the case of Gla-300, the mechanism of protraction is through microprecipitation in the subcutaneous space. Reducing the injection volume reduces the surface area of the microprecipitates and slows dissolution and absorption . However, in the case of IDeg, reducing volume does not affect the multihexamer formation or its protraction in the subcutaneous space. Therefore, IDeg 200 units/mL (IDeg-200) behaves the same as IDeg 100 units/mL (IDeg-100) .
From Physical Properties to PK/PD Profile
The mechanism of protraction has a significant impact on the PK and PD properties. When assessing these parameters, serum insulin concentration-versus-time and glucose infusion rate (GIR) are key measures. The euglycemic glucose clamp procedure is the gold standard for measuring total body glucose disposal in response to the administered test insulin to determine the PK/PD characteristics of the compound . The GIR curve depicts the glucose-metabolizing ability of any given insulin preparation over time, with the peak GIR occurring when higher levels of glucose need to be administered during the euglycemic clamp to balance the effect of the administered insulin and maintain euglycemia .
The longer time–action profiles of the second-generation basal insulin analogs require consideration of two important clinical factors—dose splitting and insulin stacking. Splitting basal insulin doses into twice-daily administration is required when the basal insulin does not provide a prolonged glucose-lowering effect over a period of 24 h. Higher doses of Gla-100, which is usually administered once daily, have been associated with longer durations of action (> 24 h) . The second-generation basal insulin analogs have longer mean durations of action (approximately 32 h for Gla-300 and at least 42 h for IDeg), and therefore do not require dose splitting , which provides a convenience advantage to the patient. With these newer formulations, a once-daily dose can be administered using a pen device that can deliver up to 160 units of Gla-300 or IDeg-200. This larger delivery dose reduces the number of injections and the number of pens required.
From PK/PD Profile to Clinical Outcomes
Second-Generation Basal Insulin Analogs Compared with First-Generation
When compared with Gla-100, Gla-300 is associated with a flatter and more consistent glucose-lowering effect, with more evenly distributed PK/PD profiles (Fig. 5). When assessed in a euglycemic clamp study, Gla-300 provided a smoother profile over a 24-h period when compared with Gla-100 (Fig. 5a) . Patients receiving Gla-300 had a significantly longer time to 50% of the area under the serum insulin and GIR curves (36 h) compared with those receiving Gla-100 (28 h), with smaller changes in steady-state concentrations and GIR up to 36 h. When assessed by continuous glucose monitoring, Gla-100 and Gla-300 had a similar time in range . Although similar profiles were seen with Gla-300 injected in the morning or the evening, larger glycemic excursions were seen for Gla-100 injected in the morning . From a clinical perspective, the EDITION program demonstrated that Gla-300 reduces the risk of hypoglycemia (severe and nocturnal confirmed), with similar glycemic control compared with Gla-100 in treat-to-target studies [20, 21, 29, 30, 31, 32]. In most of the EDITION clinical trials, annualized rates of nocturnal confirmed (< 3.9 mmol/L) or severe nocturnal hypoglycemia were lower with Gla-300 than Gla-100, with risk ratios of 0.79, 0.63, 0.89, and 0.62 for the EDITION 1, 2, 3, and JP1 trials, respectively. However, a non-significant difference in overall confirmed hypoglycemia rates was observed between Gla-300 and Gla-100 in the EDITION 4 trial (0.98–1.16) for the study as a whole. A randomized controlled study in people with T1D using continuous glucose monitoring also found that nocturnal confirmed and severe hypoglycemia rates were lower with Gla-300 than with Gla-100 (4.0 versus 9.0 events per participant-year) .
Similar to Gla-300, IDeg provided much smoother profiles over 24 h, with a considerably longer half-life than Gla-100 (Fig. 5b) . Across all doses tested in a 42-h euglycemic clamp study, IDeg GIR profiles were flatter and more stable across the assessed 6-h intervals than those for Gla-100, with estimated half-lives of 25.4 h and 12.1 h, respectively . The BEGIN program demonstrated that IDeg also reduces the risk of hypoglycemia, with similar glycemic control compared with Gla-100 in treat-to-target studies . Overall, there was a 21% lower rate of confirmed hypoglycemia (risk ratio 0.79) and a 52% lower rate of nocturnal confirmed hypoglycemia (risk ratio 0.48) with IDeg compared with Gla-100. In the SWITCH 1 and 2 clinical trials, people with T1D or type 2 diabetes (T2D) treated with IDeg had reduced rates of overall symptomatic hypoglycemia compared with those treated with Gla-100 (SWITCH 1, risk ratio 0.89; SWITCH 2, risk ratio 0.70) [35, 36]. In the DEVOTE study, participants with T2D receiving IDeg had significantly lower rates of severe hypoglycemia compared with those receiving Gla-100 (4.9% vs. 6.6%, respectively; rate ratio 0.60) .
Real-world studies of Gla-300 and IDeg have confirmed less hypoglycemia compared with Gla-100 in T2D [38, 39, 40, 41, 42]. In the DELIVER 2 and 3 studies, significantly fewer patients treated with Gla-300 experienced hypoglycemia compared with Gla-100 or IDet (adjusted odds ratio 0.75 and 0.43, respectively). Similar hypoglycemia rates were seen in patients switching to Gla-300 and IDeg from other basal insulins in the DELIVER D+ study (adjusted odds ratio 0.97). Across the EDITION clinical trials program, a higher mean dose (10–20%) of Gla-300 was required compared with Gla-100. This increase in dose is again explained by the mechanism of protraction. The microprecipitate of Gla-300, with its smaller surface area, remains in the subcutaneous space longer, presumably exposing it to tissue proteases, resulting in local degradation. As these higher dose needs are clinically relevant, they must be considered when switching from Gla-100 to Gla-300. Although randomized trials have demonstrated a higher insulin dose requirement of Gla-300, in real-world studies, the requirement is not consistent and may potentially be, at least partly, explained by differences in the treated populations . Insulin dose requirements have been assessed in the ACHIEVE CONTROL pragmatic real-life study, which compared basal insulins in insulin-naïve patients with T2D . Results show that, compared with other basal insulins used in standard of care at similar doses, patients treated with Gla-300 were more likely to achieve glycated hemoglobin targets without hypoglycemia .
Second-Generation Basal Insulin Analogs Compared with Each Other
The benefits of second-generation basal insulin analogs over first-generation are well established. Currently, comparison within class is clinically meaningful and such comparisons are emerging. In a study that compared steady-state PK and PD profiles of Gla-300 and IDeg-100 in patients with T1D, Gla-300 provided a steadier PD profile (20% lower within-day fluctuation in GIR) and a more evenly distributed PK profile (Fig. 6) at a 0.4 units/kg/day dose; however, no significant differences were seen at the higher 0.6 units/kg/day dose . A trial-level meta-analysis of the EDITION and BEGIN programs offered indirect comparison . In the DELIVER D+ study, a direct comparison of real-world clinical outcomes with Gla-300 and IDeg showed that people with T2D switching from other basal insulins to two second-generation basal insulin analogs had comparable glycemic control, and incidence and rates of hypoglycemia . Real-world analysis of electronic health records in the LIGHTNING study also demonstrated similar levels of glycemic control across basal insulins, but reported significantly lower rates of severe hypoglycemia in patients switching to Gla-300 or IDeg, compared with Gla-100 or IDet . Among insulin-naïve patients with T2D, the CONFIRM real-world analysis showed that the group receiving IDeg had less hypoglycemia, greater glycemic control, and improved insulin retention compared with Gla-300 . However, there are limitations to real-world observational analyses, with randomized controlled clinical trials needed to better understand differences between therapies. The BRIGHT study is the first head-to-head randomized controlled trial comparing Gla-300 with IDeg in insulin-naïve patients with T2D. The study demonstrated comparable levels of glycemic control with similar overall incidence and rates of hypoglycemia. However, hypoglycemia was lower with Gla-300 during the first half of the study (titration period) when the greatest glucose reduction and insulin dose increase occurred .
The time–action profile of an insulin preparation is determined by its time course and pattern of absorption and distribution from the subcutaneous injection site. Basal insulins have distinct mechanisms of protraction that give rise to equally distinct PK/PD profiles and accompanying clinical properties in people with T1D and T2D. Understanding these differential mechanisms is important to explain the clinical benefits and differences of the second-generation basal insulin analogs Gla-300 and IDeg over the earlier generation of basal insulins, Gla-100 and IDet. Gla-300 and IDeg show longer duration of action and smoother PK/PD profiles than these earlier-generation basal insulin analogs, leading to smaller glycemic excursions and a lowered risk of hypoglycemia, while retaining similar levels of glycemic control. Understanding the differences among first- and second-generation basal insulin analogs aids healthcare providers in making the most appropriate treatment decisions to address individual patient needs.
Development of the manuscript, article processing charges and the open access fee were funded by Sanofi US, Inc. All authors had full access to the articles reviewed in the manuscript and take complete responsibility for the integrity and accuracy of the manuscript.
Medical Writing and Editorial Assistance
The authors received writing/editorial support in the preparation of this manuscript provided by Rasilaben Vaghjiani, PhD, of Excerpta Medica, funded by Sanofi US, Inc.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. The sponsor also provided medical, regulatory, legal, and IP review of the final draft manuscript; suggestions were incorporated at the authors’ discretion.
Alice Cheng has received honoraria for consulting or speaking for Abbott, Astra Zeneca, Boehringer Ingelheim, HLS Therapeutics, Janssen, Merck, Novo Nordisk, and Sanofi. She is also is in clinical trial involvement with Boehringer Ingelheim, Eli Lilly, and Sanofi. Dhiren Patel has been a speaker for AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi, and Valeritas; and consulted for Becton and Dickinson, Eli Lilly, Merck, and Sanofi. Timothy Reid is a speaker/consultant for AstraZeneca, Intarcia, Janssen, Lilly, Novo Nordisk, and Sanofi-Aventis. Kathleen Wyne has consulted for AstraZeneca and Sanofi.
Compliance with Ethics Guidelines
This article does not contain any studies with human participants or animals performed by any of the authors.
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
- 4.Anderson JE. An evolutionary perspective on basal insulin in diabetes treatment: innovations in insulin: insulin glargine U-300. J Fam Pract. 2016;65:S23–8.Google Scholar
- 10.Bailey TS, Pettus J, Roussel R, et al. Morning administration of 0.4U/kg/day insulin glargine 300U/mL provides less fluctuating 24-hour pharmacodynamics and more even pharmacokinetic profiles compared with insulin degludec 100U/mL in type 1 diabetes. Diabetes Metab. 2018;44:15–21.CrossRefGoogle Scholar
- 16.Aye MM, Atkin SL. Patient safety and minimizing risk with insulin administration–role of insulin degludec. Drug Healthc Patient Saf. 2014;6:55–67.Google Scholar
- 18.Tresiba® dosing and device. https://www.tresibapro.com/dosing-and-device/starting-patients.html. Accessed 23 Feb 2019.
- 19.Toujeo® insulin dosing and titration calculator. https://www.toujeopro.com/toujeo-insulin-dosing-and-titration-calculator. Accessed 23 Feb 2019.
- 20.Riddle MC, Bolli GB, Ziemen M, et al. New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using basal and mealtime insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 1). Diabetes Care. 2014;37:2755–62.CrossRefGoogle Scholar
- 23.Yki-Järvinen H, Bergenstal R, Ziemen M, et al. New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using oral agents and basal insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 2). Diabetes Care. 2014;37:3235–43.CrossRefGoogle Scholar
- 24.Davies M, Bain S, Charpentier G, et al. A randomized controlled, treat-to-target study evaluating the efficacy and safety of insulin glargine 300 U/mL (Gla-300) administered using either device-supported or routine titration in people with type 2 diabetes. J Diabetes Sci Technol. 2019. https://doi.org/10.1177/1932296818821706.
- 26.Strojek K, Bigot G, Bonnemaire M, et al. Self- vs. physician-led titration of insulin glargine 300 U/mL (Gla-300)—improved or comparable efficacy at week 24 without increased risk of hypoglycemia, irrespective of age (< 65 or = 65 years)—TAKE CONTROL. Diabetes. 2018;67(Suppl 1):A81.Google Scholar
- 27.Becker RH, Dahmen R, Bergmann K, Lehmann A, Jax T, Heise T. New insulin glargine 300 units/mL provides a more even activity profile and prolonged glycemic control at steady state compared with insulin glargine 100 units/mL. Diabetes Care. 2015;38:637–43.Google Scholar
- 31.Yki-Järvinen H, Bergenstal RM, Bolli GB, et al. Glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus insulin glargine 100 U/ml in people with type 2 diabetes using basal insulin and oral antihyperglycaemic drugs: the EDITION 2 randomized 12-month trial including 6-month extension. Diabetes Obes Metab. 2015;17:1142–9.CrossRefGoogle Scholar
- 32.Matsuhisa M, Koyama M, Cheng X, et al. Sustained glycaemic control and less nocturnal hypoglycaemia with insulin glargine 300U/mL compared with glargine 100U/mL in Japanese adults with type 1 diabetes (EDITION JP 1 randomised 12-month trial including 6-month extension). Diabetes Res Clin Pract. 2016;122:133–40.CrossRefGoogle Scholar
- 34.Rodbard HW, Gough S, Lane W, Korsholm L, Bretler DM, Handelsman Y. Reduced risk of hypoglycemia with insulin degludec versus insulin glargine in patients with type 2 diabetes requiring high doses of basal insulin: a meta-analysis of 5 randomized begin trials. Endocr Pract. 2014;20:285–92.CrossRefGoogle Scholar
- 39.Zhou FL, Ye F, Gupta V, et al. Lower risk of hypoglycemia after switch to insulin glargine 300 U/mL (Gla-300) vs other basal insulins in patients with type 2 diabetes (T2D) on basal insulin in real-world clinical settings (Deliver 2 study). Poster presented at the Endocrine Society 2017 Annual Meeting (ENDO 2017), Orlando, FL, USA; April 1–4, 2017; poster LB SUN 81.Google Scholar
- 40.Zhou FL, Ye F, Gupta V, et al. Older adults with type 2 diabetes (T2D) experience less hypoglycemia when switching to insulin glargine 300 U/mL (Gla-300) vs other basal insulins (DELIVER 3 Study). Poster presented at the American Diabetes Association (ADA) 77th Scientific Sessions, San Diego, CA, USA; June 10, 2017; poster 986-P.Google Scholar
- 41.Bailey TS, Zhou FL, Gupta R, et al. Glycemic goal attainment and hypoglycemia risk outcomes in patients with T2D intiating insulin glargine 300 U/mL vs 100 U/mL in real-world clinical practice. Poster presented at the 2018 Annual Meeting of the Academy of Managed Care Pharmacy (AMCP), Boston, MA, USA; April 23–26, 2018; poster E13.Google Scholar
- 42.Sullivan SD, Bailey TS, Roussel R, et al. Clinical outcomes in real-world patients with type 2 diabetes switching from first- to second-generation basal insulin analogues: comparative effectiveness of insulin glargine 300 units/mL and insulin degludec in the DELIVER D+ cohort study. Diabetes Obes Metab. 2018;20:2148–58.CrossRefGoogle Scholar
- 43.Bohn B, Bramlage P, Wagner C, et al. Which patients from routine care use the new insulin analogue glargine U300 compared to patients with glargine U100: a multicenter analysis of 14,123 patients with insulin glargine from die diabetes registries DPV and DIVE. Wien Med Wochenschr. 2018;168:415–22.CrossRefGoogle Scholar
- 44.Meneghini L, Sullivan S, Oster G, et al. A randomized prospective pragmatic real-world clinical trial of insulin glargine 300 u/ml versus other basal insulins in insulin-naive patients with type 2 diabetes: a 6-month analysis of the achieve control study. J Manag Care Pharm. 2018;24:S18.Google Scholar
- 46.Meneghini L, Zhou FL, Bosnyak Z, et al. Hypoglycemia risk associated with basal insulin use in type 2 diabetes (T2DM): the LIGHTNING study. Poster presented at the 11th Annual Conference on Advanced Technologies and Treatments for Diabetes (ATTD), Vienna, Austria; February 1, 2018; poster ATTD8-0420.Google Scholar
- 47.Tibaldi JM, Haldrup S, Sandberg V, Wolden ML, Rodbard HW. Clinical outcome assessment of the effectiveness of insulin degludec (degludec) in real-life medical practice (CONFIRM) – a comparative effectiveness study of degludec and insulin glargine 300U/mL (Glargine U300) in insuline-naïve patients with type 2 diabetes (T2D). Diabetes. 2018;67(Suppl 1):LB27.Google Scholar
Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.