Insulin therapy has advanced remarkably over the past few decades. Ultra-rapid-acting and ultra-long-acting insulin analogs are now commercially available. Many additional insulin formulations are in development. This review outlines recent advances in insulin therapy and novel therapies in development.
Get full access to this article
View all access options for this article.
References
1.
Centers for Disease Control and Prevention: National Diabetes Statistics Report, 2017: Atlanta, GA: Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, 2017.
2.
SaydahSH: Medication use and self care practices in person with diabetes. In: Cowie CC, Casagrande SS, Menke A, et al., eds. Diabetes in America, 3rd ed. Bethesda, MD: National Institutes of Health, 2017.
3.
CobryE, McFannK, MesserL, et al.: Timing of meal insulin boluses to achieve optimal postprandial glycemic control in patients with type 1 diabetes. Diabetes Technol Ther, 2010; 12:173–177.
4.
CryerPE: Mechanisms of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med, 2013; 369:362–372.
5.
JansenHJ, VervoortGM, de HaanAF, et al.: Diabetes-related distress, insulin dose, and age contribute to insulin-associated weight gain in patients with type 2 diabetes: results of a prospective study. Diabetes Care, 2014; 37:2710–2717.
6.
PeyrotM, RubinRR, KrugerDF, TravisLB: Correlates of insulin injection omission. Diabetes Care, 2010; 33:240–245.
7.
HerkertD, VijayakumarP, LuoJ, et al.: Cost-related insulin underuse among patients with diabetes. JAMA Intern Med, 2019; 179:112–114.
8.
BeckerRH, DahmenR, BergmannK, et al.: New insulin glargine 300 Units.mL-1 provides a more even activity profile and prolonged glycemic control at steady state compared with insulin glargine 100 Units. Diabetes Care, 2015; 38:637–643.
9.
RiddleMC, BolliGB, ZiemenM, 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; 37:2755–2762.
10.
Yki-JarvinenH, BergenstalRM, BolliGB, 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; 17:1142–1149.
11.
RiddleMC, BolliGB, HomePD, et al.: Efficacy and safety of flexible versus fixed dosing intervals of insulin glargine 300 u/ml in people with type 2 diabetes. Diabetes Technol Ther, 2016; 18:252–257.
12.
Tresiba prescribing information: Available at https://www.novo-pi.com/tresiba.pdf (accessed January3, 2020).
13.
HeiseT, HermanskiL, NosekL, et al.: Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady-state conditions in type 1 diabetes. Diabetes Obes Metab, 2012; 14:859–864.
14.
MeneghiniL, AtkinSL, GoughSC, et al.: The efficacy and safety of insulin degludec given in variable once-daily dosing intervals compared with insulin glargine and insulin degludec dosed at the same time daily: a 26-week, randomized, open-label, parallel-group, treat-to-target trial in individuals with type 2 diabetes. Diabetes Care, 2013; 36:858–864.
15.
MathieuC, HollanderP, Miranda-PalmaB, et al.: Efficacy and safety of insulin degludec in a flexible dosing regimen vs insulin glargine in patients with type 1 diabetes (BEGIN: Flex T1): a 26-week randomized, treat-to-target trial with a 26-week extension. J Clin Endocrinol Metab, 2013; 98:1154–1162.
16.
LaneW, BaileyTS, GeretyG, et al.: Effect of insulin degludec vs insulin glargine u100 on hypoglycemia in patients with type 1 diabetes: the SWITCH 1 randomized clinical trial. JAMA, 2017; 318:33–44.
17.
WyshamC, BhargavaA, ChaykinL, et al.: Effect of insulin degludec vs insulin glargine u100 on hypoglycemia in patients with type 2 diabetes: the SWITCH 2 randomized clinical trial. JAMA, 2017; 318:45–56.
18.
MarsoSP, McGuireDK, ZinmanB, et al.: Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med, 2017; 377:723–732.
19.
HeiseT, NorskovM, NosekL, et al.: Insulin degludec: Lower day-to-day and within-day variability in pharmacodynamic response compared with insulin glargine 300 U/mL in type 1 diabetes. Diabetes Obes Metab, 2017; 19:1032–1039.
20.
RosenstockJ, ChengA, RitzelR, et al.: More similarities than differences testing insulin glargine 300 Units/mL versus insulin degludec 100 Units/mL in insulin-naive type 2 diabetes: the randomized head-to-head BRIGHT trial. Diabetes Care, 2018; 41:2147–2154.
21.
Philis-TsimikasA, KlonoffDC, KhuntiK, et al.: Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: the randomised, head-to-head CONCLUDE trial. Diabetologia, 2020; 63:698–710.
22.
CooperH, TekitekiA, KhanolkarM, BraatvedtG: Risk factors for recurrent admissions with diabetic ketoacidosis: a case-control observational study. Diabet Med, 2016; 33:523–528.
23.
DaviesMJ, Russell-JonesD, SelamJL, et al.: Basal insulin peglispro versus insulin glargine in insulin-naive type 2 diabetes: IMAGINE 2 randomized trial. Diabetes Obes Metab, 2016; 18:1055–1064.
24.
EldorR, ArbitE, CorcosA, et al.: Glucose-reducing effect of the ORMD-0801 oral insulin preparation in patients with uncontrolled type 1 diabetes: a pilot study. PLoS One, 2013; 8:e59524.
25.
HalbergIB, LybyK, WassermannK, et al.: Efficacy and safety of oral basal insulin versus subcutaneous insulin glargine in type 2 diabetes: a randomised, double-blind, phase 2 trial. Lancet Diabetes Endocrinol, 2019; 7:179–188.
26.
U.S. Food and Drug Administration: Approval package for: Fiasp 100 units/mL. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208751Orig1s000Approv.pdf (accessed December13, 2019).
27.
KildegaardJ, BuckleyST, NielsenRH, et al.: Elucidating the mechanism of absorption of fast-acting insulin aspart: the role of niacinamide. Pharm Res, 2019; 36:49.
28.
U.S. Food and Drug Administration: Inactive ingredient search for approved drug products. https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm (accessed November27, 2019).
29.
HeiseT, PieberTR, DanneT, et al.: A pooled analysis of clinical pharmacology trials investigating the pharmacokinetic and pharmacodynamic characteristics of fast-acting insulin aspart in adults with type 1 diabetes. Clin Pharmacokinet, 2017; 56:551–559.
30.
Russell-JonesD, BodeBW, De BlockC, et al.: Fast-acting insulin aspart improves glycemic control in basal-bolus treatment for type 1 diabetes: results of a 26-week multicenter, active-controlled, treat-to-target, randomized, parallel-group trial (Onset 1). Diabetes Care, 2017; 40:943–950.
31.
BoweringK, CaseC, HarveyJ, et al.: Faster aspart versus insulin aspart as part of a basal-bolus regimen in inadequately controlled type 2 diabetes: the Onset 2 Trial. Diabetes Care, 2017; 40:951–957.
32.
Rayhan LalM, Liana HsuB, Marina BasinaM, Bruce BuckinghamM: Fiasp® (fast-acting insulin aspart) use with a Medtronic 670G system. 19th Annual Diabetes Technology Meeting; November 14–16, 2019; Bethesda, MD.
33.
StevenJ. Russell M, Rabab Jafri M, et al.: Use of the ultra-rapid insulin Fiasp in the iLet bionic pancreas. 19th Annual Diabetes Technology Meeting; November 14–16, 2019; Bethesda, MD.
34.
HeinemannL, BaughmanR, BossA, HompeschM: Pharmacokinetic and pharmacodynamic properties of a novel inhaled insulin. J Diabetes Sci Technol, 2017; 11:148–156.
35.
HeinemannL, ParkinCG: Rethinking the viability and utility of inhaled insulin in clinical practice. J Diabetes Res, 2018; 2018:4568903.
36.
PettusJ, Santos CavaiolaT, EdelmanSV: Recommendations for initiating use of Afrezza inhaled insulin in individuals with type 1 diabetes. Diabetes Technol Ther, 2018; 20:448–451.
37.
U.S. Food and Drug Administration: AFREZZA® (insulin human) inhalation powder. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022472lbl.pdf (accessed December13, 2019).
38.
RaveK, HeiseT, PfutznerA, BossAH: Coverage of postprandial blood glucose excursions with inhaled technosphere insulin in comparison to subcutaneously injected regular human insulin in subjects with type 2 diabetes. Diabetes Care, 2007; 30:2307–2308.
39.
PittasAG, WestcottGP, BalkEM: Efficacy, safety, and patient acceptability of Technosphere inhaled insulin for people with diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol, 2015; 3:886–894.
Eric ZijlstraP, Leona Plum-MoerschelM, Marcel ErmerM, et al.: Faster absorption and greater early insulin action of Dance 501 inhaled human insulin vs. s.c. insulin lispro in patients with type 2 diabetes. 19th Annual Diabetes Technology Meeting; November 14–16, 2019; Bethesda, MD.
42.
Eric ZijlstraP, Oliver KleinM, Felix SieversM, et al.: Dance 501 inhaled human insulin: lineardose response in patients with type 1 diabetes. 19th Annual Diabetes Technology Meeting; November 14–16, 2019; Bethesda, MD.
43.
BlevinsT, ZhangQ, FriasJP, et al.: Ultra Rapid Lispro improves postprandial glucose control vs. humalog (lispro) in patients with type 2 diabetes: PRONTO-T2D. American Diabetes Associations 79th Scientific Sessions; June 7–11, 2019; San Francisco, CA.
44.
BodeBW, CaoD, LiuR, et al.: Ultra Rapid Lispro improves postprandial glucose control and time in range in T1D compared with Humalog (lispro): PRONTO-T1D continuous glucose monitoring (CGM) Substudy. American Diabetes Associations 79th Scientific Sessions; June 7–11, 2019; San Francisco, CA.
45.
KlaffLJ, CaoD, DellvaMA, et al.: Ultra Rapid Lispro improves postprandial glucose control vs. Humalog (lispro) in T1D: PRONTO-T1D Study. American Diabetes Associations 79th Scientific Sessions; June 7–11, 2019; San Francisco, CA.
46.
LeohrJ, DellvaMA, CoutantDE, et al.: Ultra Rapid Lispro accelerates insulin lispro absorption and insulin action vs. Humalog (lispro) in patients with T2D. American Diabetes Associations 79th Scientific Sessions; June 7–11, 2019; San Francisco, CA.
47.
LinnebjergH, ZhangQ, LabellES, et al.: Ultra Rapid Lispro accelerates insulin lispro absorption and insulin action vs. Humalog (lispro) in patients with T1D. American Diabetes Associations 79th Scientific Sessions; June 7–11, 2019; San Francisco, CA.
48.
HeiseT, LinnebjergH, CaoD, et al.: Ultra Rapid Lispro lowers postprandial glucose and more closely matches normal physiological glucose response compared with other rapid insulin analogs. American Diabetes Associations 79th Scientific Sessions; June 7–11, 2019; San Francisco, CA.
AndersenG, MeiffrenG, LamersD, et al.: 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. Diabetes Obes Metab, 2018; 20:2627–2632.
51.
HeiseT, MeiffrenG, AlluisB, et al.: BioChaperone Lispro versus faster aspart and insulin aspart in patients with type 1 diabetes using continuous subcutaneous insulin infusion: A randomized euglycemic clamp study. Diabetes Obes Metab, 2019; 21:1066–1070.
52.
MeiffrenG, HerbrandT, AnastassiadisE, et al.: Better glycaemic 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. Diabetes Obes Metab, 2019; 21:1570–1575.
53.
PieberTR, HowellSJ, JezekJ, GerringDJ: Pharmacokinetic and pharmacodynamic properties of a novel “superfast” insulin aspart formulation. American Diabetes Associations 78th Scientific Sessions; June 22–26, 2018; Orlando, FL.
54.
Arecor: 5/12/2019- Arecor announces positive headline results for the first phase I clinical trial ofAT, a novel ultra rapid acting formulation of insulin. http://arecor.com/news (accessed December13, 2019).
55.
ButlerPC, ChouJ, CarterWB, et al.: Effects of meal ingestion on plasma amylin concentration in NIDDM and nondiabetic humans. Diabetes, 1990; 39:752–756.
56.
SchmitzO, BrockB, RungbyJ: Amylin agonists: a novel approach in the treatment of diabetes. Diabetes, 2004; 53Suppl 3:S233–S238.
57.
RyanG, BriscoeTA, JobeL: Review of pramlintide as adjunctive therapy in treatment of type 1 and type 2 diabetes. Drug Des Devel Ther, 2009; 2:203–214.
58.
HollanderPA, LevyP, FinemanMS, et al.: Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care, 2003; 26:784–790.
59.
WeinzimerSA, SherrJL, CengizE, et al.: Effect of pramlintide on prandial glycemic excursions during closed-loop control in adolescents and young adults with type 1 diabetes. Diabetes Care, 2012; 35:1994–1999.
60.
HaidarA, TsoukasMA, Bernier-TwardyS, YaleJF, RutkowskiJ, BossyA, PytkaE, El FathiA, StraussN, LegaultL. A novel dual-hormone insulin-and-pramlintide artificial pancreas for type 1 diabetes: a randomized controlled crossover trial. Diabetes Care 2020 Mar, 1; 43:597–606.
61.
MeiffrenG, SeroussiC, RansonA, et al.: BioChaperone Pramlintide Insulin, a new co-formulation of pramlintide (pram) and human insulin (ins), improves postprandial blood glucose (BG) vs. both separate injections of pram+ins and insulin lispro (lis) in subjects with T1D. American Diabetes Associations 79th Scientific Sessions; June 7–11, 2019; San Francisco, CA.
62.
ThohanS, HuWT, DonovanMJ, et al.: Glycemic control with pramlintide and insulin coformulations: preclinical evaluation of a novel single injection, room temperature stable formulation. American Diabetes Associations 79th Scientific Sessions; June 7–11, 2019; San Francisco, CA.
63.
AhorukomeyeP, DisotuarMM, GajewiakJ, et al.: Fish-hunting cone snail venoms are a rich source of minimized ligands of the vertebrate insulin receptor. Elife, 2019; 8:pii: e41574.
64.
BanerjeeA, IbsenK, BrownT, et al.: Ionic liquids for oral insulin delivery. Proc Natl Acad Sci U S A, 2018; 115:7296–7301.
65.
SharmaG, SharmaAR, NamJS, et al.: Nanoparticle based insulin delivery system: the next generation efficient therapy for type 1 diabetes. J Nanobiotechnology, 2015; 13:74.
66.
BanerjeeA, WongJ, GogoiR, et al.: Intestinal micropatches for oral insulin delivery. J Drug Target, 2017; 25:608–615.
67.
AbramsonA, Caffarel-SalvadorE, SoaresV, et al.: A luminal unfolding microneedle injector for oral delivery of macromolecules. Nat Med, 2019; 25:1512–1518.
68.
GedawyA, MartinezJ, Al-SalamiH, DassCR: Oral insulin delivery: existing barriers and current counter-strategies. J Pharm Pharmacol, 2018; 70:197–213.
69.
KlonoffDC, BodeBW, CohenNJ, et al.: Divergent hypoglycemic effects of hepatic directed prandial insulin: a 6-month study in type 1 diabetes mellitus (T1DM). American Diabetes Associations 79th Scientific Sessions; June 7–11, 2019; San Francisco, CA.
70.
KlonoffD, BodeB, CohenN, et al.: Divergent hypoglycemic effects of hepatic-directed prandial insulin: a 6-month phase 2b study in type 1 diabetes. Diabetes Care, 2019; 42:2154–2157.
71.
YuJ ZY, BombaH, GuZ: Stimuli-responsive delivery of therapeutics for diabetes treatment. Bioeng Transl Med, 2016; 1:323–337.
72.
VandenBergMA, WebberMJ: Biologically inspired and chemically derived methods for glucose-responsive insulin therapy. Adv Healthc Mater, 2019; 8:e1801466.
73.
BallerstadtR, EvansC, McNicholsR, GowdaA: Concanavalin A for in vivo glucose sensing: a biotoxicity review. Biosens Bioelectron, 2006; 22:275–284.
74.
KrugAW, VisserSAG, TsaiK, et al.: Clinical evaluation of MK-2640: An insulin analog with glucose-responsive properties. Clin Pharmacol Ther, 2019; 105:417–425.
75.
KaarsholmNC, LinS, YanL, et al.: Engineering glucose responsiveness into insulin. Diabetes, 2018; 67:299–308.
76.
ParkEJ, WernerJ, SmithNB: Ultrasound mediated transdermal insulin delivery in pigs using a lightweight transducer. Pharm Res, 2007; 24:1396–1401.
77.
KwokCS, MouradPD, CrumLA, RatnerBD: Self-assembled molecular structures as ultrasonically-responsive barrier membranes for pulsatile drug delivery. J Biomed Mater Res, 2001; 57:151–164.
78.
DiJ, PriceJ, GuX, et al.: Ultrasound-triggered regulation of blood glucose levels using injectable nano-network. Adv Healthc Mater, 2014; 3:811–816.
NoseK, PissuwanD, GotoM, et al.: Gold nanorods in an oil-base formulation for transdermal treatment of type 1 diabetes in mice. Nanoscale, 2012; 4:3776–3780.
81.
TimkoBP, ArrueboM, ShankarappaSA, et al.: Near-infrared-actuated devices for remotely controlled drug delivery. Proc Natl Acad Sci U S A, 2014; 111:1349–1354.
82.
KloudaL: Thermoresponsive hydrogels in biomedical applications: a seven-year update. Eur J Pharm Biopharm, 2015; 97:338–349.
83.
StuartMA, HuckWT, GenzerJ, et al.: Emerging applications of stimuli-responsive polymer materials. Nat Mater, 2010; 9:101–113.
84.
LimaAC, SongW, Blanco-FernandezB, et al.: Synthesis of temperature-responsive dextran-MA/PNIPAAm particles for controlled drug delivery using superhydrophobic surfaces. Pharm Res, 2011; 28:1294–1305.
85.
LeeH, ChoiTK, LeeYB, et al.: A graphene-based electrochemical device with thermoresponsive microneedles for diabetes monitoring and therapy. Nat Nanotechnol, 2016; 11:566–572.
86.
CengizE, WeinzimerSA, SherrJL, et al.: Faster in and faster out: accelerating insulin absorption and action by insulin infusion site warming. Diabetes Technol Ther, 2014; 16:20–25.