Indication
Type 2 diabetes mellitus
ICD11 code:
5A11
Medicine type
Biological agent
List type
Core
Formulations
Parenteral > General injections > SC:
100 IU per 1 mL in 10 mL vial ;
100 IU per 1 mL in 3 mL cartridge ;
100 IU per 1 mL in 3 mL pre-filled pen
EML status history
First added in 2025
(TRS
1064)
Sex
All
Age
Adolescents and adults
Therapeutic alternatives
insulin lispro
(ATC codes: A10AB04)
Parenteral > General injections > SC: 100 IU per mL in 10 mL vial; 100 IU per mL in 3 mL cartridge; 100 IU per mL in 3 mL pre-filled pen
Parenteral > General injections > SC: 100 IU per mL in 10 mL vial; 100 IU per mL in 3 mL cartridge; 100 IU per mL in 3 mL pre-filled pen
insulin aspart
(ATC codes: A10AB05)
Parenteral > General injections > SC: 100 IU per mL in 10 mL vial; 100 IU per mL in 3 mL cartridge; 100 IU per mL in 3 mL pre-filled pen
Parenteral > General injections > SC: 100 IU per mL in 10 mL vial; 100 IU per mL in 3 mL cartridge; 100 IU per mL in 3 mL pre-filled pen
insulin glulisine
(ATC codes: A10AB06)
Parenteral > General injections > SC: 100 IU per mL in 10 mL vial; 100 IU per mL in 3 mL cartridge; 100 IU per mL in 3 mL pre-filled pen
Parenteral > General injections > SC: 100 IU per mL in 10 mL vial; 100 IU per mL in 3 mL cartridge; 100 IU per mL in 3 mL pre-filled pen
Patent information
Read more
about patents.
Wikipedia
Expert Committee recommendation
The Expert Committee recognized the importance of affordable and equitable access to insulin products as a public health priority.
The Committee considered that the available evidence indicates generally comparable efficacy and safety between rapid-acting insulin analogues and regular human insulin. The Committee noted that some studies provided evidence of higher patient satisfaction scores with rapid-acting insulin analogues and others suggest that rapid-acting insulin analogues may be associated with lower rates of complications, with medicine costs offset by reduced demand for high-cost treatments and health services for complications, particularly in type 1 diabetes. However, the Committee considered these benefits were tenuous and did not provide compelling arguments to support the inclusion of rapid-acting insulin analogues on the Model Lists.
The Committee recognized that rapid-acting insulin analogues may be more expensive than regular human insulin and may be less affordable in some resource-constrained settings. However, in other settings the prices of rapid-acting insulin analogues do not exceed the price of regular human insulin. The Committee noted that larger insulin markets could help stabilize prices, secure supply chains of quality-assured products and mitigate the risks of shortages. In countries where insulin prices are excessive, consideration should be given to strengthening the regulatory framework, implementing or maintaining price control, or reference-pricing mechanisms. The outcomes of price controls and reference pricing for essential medicines should be closely monitored as these policies can have unintended consequences, e.g. shortages. The Committee emphasized the importance of commitment and action from WHO, Member States, insulin producers, procurement agencies and other stakeholders to address the problem of equitable and affordable access to insulin products globally. The Committee highlighted the need for multipronged policy, pricing and procurement strategies to strengthen affordable access.
In consideration of access to insulin, the Committee noted with concern the progressive withdrawal of regular human insulin from markets. The Committee acknowledged the concerns of the WHO technical department that the inclusion of rapid-acting insulin analogues might adversely affect the ongoing availability of regular human insulin, particularly in the most resource-constrained settings. However, the Committee also noted that in the case of insulin, EML-listing was unlikely to be the strongest or most influential driver of market access nor to revive the marginal sales of human insulin. The Committee emphasized that no changes were being made to the status of human insulins on the Model Lists.
The Committee considered that the inclusion of rapid-acting insulin analogues would serve to increase the number of insulin products on the Model Lists and would complement the listing of long-acting insulin analogues for use in basal-bolus regimens. This is consistent with the listings for short- and intermediate-acting human insulins.
Based on these considerations, the Expert Committee recommended the inclusion of rapid-acting insulin analogues (insulin aspart, insulin glulisine and insulin lispro, and their quality-assured biosimilars, as therapeutic alternatives) on the core list of the EML and EMLc for the treatment of people with type 1 and type 2 diabetes, and people with gestational diabetes.
Background
Rapid-acting insulin analogues have not previously been evaluated for inclusion on the Model Lists.
The Model Lists currently include human insulin (short- and intermediate-acting) and long-acting insulin analogues.
Public health relevance
The public health relevance of insulin in the treatment of diabetes is well established.
According to data from the Global Burden of Disease study, diabetes mellitus affected 525.6 million people globally in 2021. Most cases were type 2 diabetes (506 million). The disease was responsible for more than 1.6 million deaths and 2.7% of global disability-adjusted life years (1). A 2021 study estimated the global prevalence of gestational diabetes to be 14.0% (2).
Benefits
Type 1 diabetes
A 2016 Cochrane systematic review of nine randomized controlled trials (2693 participants) assessed the effects of rapid-acting insulin analogues versus regular human insulin in non-pregnant adults with type 1 diabetes (3). Six studies involved insulin lispro and three studies involved insulin aspart. For the secondary outcome of glycaemic control, the mean difference (MD) in glycated haemoglobin (HbA1c) favoured rapid-acting insulin analogues (MD −0.15% (95% confidence interval (CI) −0.21% to −0.08%; nine randomized controlled trials, 2608 participants; low-quality evidence). No data on all-cause mortality or micro- and macrovascular complications were reported in the trials.
A 2018 systematic review and meta-analysis assessed the efficacy and safety rapid-acting insulin analogues in children and adolescents (five randomized controlled trials) and people using continuous subcutaneous insulin infusion (six randomized controlled trials) with type 1 diabetes (4). The review also identified seven randomized controlled trials in pregnancy, but these were not included in the quantitative meta-analysis due to heterogeneity. Among children and adolescent trials, no significant difference was found between rapid-acting insulin analogues and regular human insulin for severe hypoglycaemic events (risk difference (RD) 0.00, 95% CI −0.01 to 0.01; five randomized controlled trials, 1216 participants). Among the trials on continuous subcutaneous insulin infusion, rapid-acting insulin analogues led to greater lowering of postprandial plasma glucose than regular human insulin (MD −1.63 mmol/L, 95% CI −1.71 to −1.54 mmol/L,; five randomized controlled trials, 460 participants), but no significant differences were found between treatment groups for fasting plasma glucose (MD −0.53 mmol/L, 95% CI −1.21 to 0.15 mmol/L; three randomized controlled trials, 324 participants), severe hypoglycaemic episodes (RD −0.01, 95% CI −0.04 to 0.02; seven randomized controlled trials, 553 participants), the rate of any hypoglycaemic episode (RD −0.75, 95% CI −2.21 to 0.72; five randomized controlled trials 232 participants) or difference in HbA1c (MD −0.19%, 95% CI −0.46% to 0.08%; five randomized controlled trials, 451 participants).
A 2019 systematic review and meta-analysis of 22 randomized controlled trials (6235 participants) evaluated the effects of rapid-acting insulin analogues versus regular human insulin in children, adolescents and adults with type 1 diabetes (5). Primary outcomes were hypoglycaemia and postprandial glucose levels. HbA1c and quality of life were secondary outcomes. Rapid-acting insulin analogues were associated with lower postprandial glucose levels (MD −19.44 mg/dL, 95% CI −21.49 to −17.39; 15 randomized controlled trials, 5031 participants) compared with regular human insulin. For the outcome of HbA1c, pooled data from 15 randomized controlled trials (5204 participants) showed insulin aspart and insulin lispro to be associated with lower HbA1c levels compared with regular human insulin (MD −0.13%, 95% CI −0.16% to −0.10%). However, when assessed separately, only insulin aspart was associated with lower HbA1c compared with regular human insulin.
Type 2 diabetes
A 2018 Cochrane systematic review of 10 randomized controlled trials (2751 participants) assessed the effects of rapid-acting insulin analogues versus regular human insulin in non-pregnant adults with type 2 diabetes (6). For the primary outcome of all-cause mortality, mortality events were rare but occurred more frequently in the insulin analogue group (0.4% versus 0.2%, Peto odds ratio (OR) 1.66, 95% CI 0.47 to 6.64; three randomized controlled trials, 2519 participants; moderate-certainty evidence). No differences were observed between different types of insulin analogues nor between treatment groups for severe hypoglycaemic events (outcomes not meta-analysed). For the secondary outcome of glycaemic control, no significant difference was seen between treatment groups in the change in HbA1c (MD −0.03%, 95% CI −0.16% to 0.09%); nine randomized controlled trials, 2608 participants; low-certainty evidence), with no differences observed between different types of insulin analogues.
Pregnant women with pre-existing diabetes and gestational diabetes
A 2017 Cochrane systematic review of five randomized controlled trials (554 women and babies) evaluated different insulin types and regimens in pregnant women with pre-existing type 1 or type 2 diabetes (7). Two of the included trials compared rapid-acting insulin analogues with regular human insulin, only one of which reported on outcome measures of interest of the review. For the main comparison of insulin lispro versus regular human insulin (one randomized controlled trial, 33 participants), there was very-low-quality evidence of no significant differences between treatment groups for perinatal death (relative effect not estimable), preeclampsia (risk ratio (RR) 0.68, 95% CI 0.35 to 1.30), caesarean section (RR 0.59, 95% CI 0.25 to 1.39) and birth trauma (relative effect not estimable).
The 2018 systematic review that assessed efficacy and safety of rapid-acting insulin analogues in special populations with type 1 diabetes included two randomized controlled trials in people with pre-gestational type 1 diabetes and four randomized controlled trials in people with gestational diabetes (4). The results generally showed similar outcomes with rapid-acting insulin analogues and regular human insulin for glycaemic control, hypoglycaemic events and neonatal outcomes. In pregnant women with pre-existing type 1 diabetes, the largest trial randomized 322 women to receive insulin aspart or regular human insulin in combination with neutral protamine Hagedorn basal insulin and found that HbA1c levels were comparable between treatment arms at the end of the second and third trimesters. Postprandial plasma glucose increments, and mean plasma glucose levels at 90 minutes post-breakfast were significantly lower for insulin aspart. Insulin aspart was associated with a non-significant reduction in risk of major hypoglycaemic events (RR 0.72, 95% CI 0.36 to 1.46). Among trials in women with gestational diabetes, the results generally indicated insulin lispro to be at least as effective as or more effective than regular human insulin for glycaemic control.
Harms
Type 1 diabetes
From the 2016 Cochrane systematic review in type 1 diabetes, for the outcome of severe hypoglycaemic episodes, rapid-acting insulin analogues were associated with a non-significant reduced risk of severe hypoglycaemia compared with human insulin (OR 0.89, 95% CI 0.71 to 1.12; seven randomized controlled trials, 2459 participants, very-low-quality evidence). For the outcome of weight gain, no significant difference was seen between treatment groups (MD −0.11 kg, 95% CI −0.25 kg to 0.04 kg; six randomized controlled trials, 2385 participants, moderate-quality evidence) (3).
From the 2018 systematic review in special populations with type 1 diabetes, among children and adolescent trials, no significant difference was seen between rapid-acting insulin analogues and regular human insulin for severe hypoglycaemic events (risk difference (RD) 0.00, 95% CI −0.01 to 0.01; five randomized controlled trials, 1216 participants, low-quality evidence) (4). Among the trials on continuous subcutaneous insulin infusion, no significant differences were seen between treatment groups for severe hypoglycaemic episodes (RD −0.01, 95% CI −0.04 to 0.02; seven randomized controlled trials, 553 participants) or any hypoglycaemic episode (RD −0.75, 95% CI −2.21 to 0.72; five randomized controlled trials 232 participants).
From the 2019 systematic review, results for all hypoglycaemic episodes per month showed no difference between rapid-acting insulin analogues and human insulin (risk rate (RR) 0.94, 95% CI 0.89 to 1.00; 22 randomized controlled trials, 6235 participants). However, in a sensitivity analysis excluding studies with a high risk of bias, rapid-acting insulin analogues were associated with fewer hypoglycaemic events per month compared with regular human insulin (RR 0.93, 95% CI 0.87 to 0.99; 20 randomized controlled trials, 6180 participants). Rapid-acting insulin analogues were associated with a reduced risk of nocturnal hypoglycaemia (RR 0.55, 95% CI 0.40 to 0.76; eight randomized controlled trials, 1995 participants) and severe hypoglycaemia (RR 0.68, 95% CI 0.60 to 0.77; 15 randomized controlled trials, 5945 participants) compared with regular human insulin (5).
Type 2 diabetes
From the 2016 Cochrane systematic review in type 2 diabetes, for the primary outcome of all-cause mortality, mortality events were rare but occurred more frequently in the insulin analogue group (0.4% versus 0.2%, Peto OR 1.66, 95% CI 0.47 to 6.64; three randomized controlled trials, 2519 participants; moderate-certainty evidence). No differences were observed between different types of insulin analogues nor between treatment groups for severe hypoglycaemic events (outcome not meta-analysed) (6).
Cost / cost effectiveness
The application identified and summarized the findings of 19 research articles considering cost, cost–effectiveness, budget impact and price of insulin (9–27). Most studies were conducted in high-income settings and published more than 5 years ago.
In summary, the application highlighted that rapid-acting insulin analogues are more expensive than regular human insulin in various settings, although production costs are relatively similar. The growing availability of biosimilars offers opportunities for price reductions. Despite higher upfront costs, insulin analogues may result in lower overall health-care costs due to a reduced incidence of hypoglycaemia, fewer hospitalizations and lower rates of diabetes-related complications. Cost–effectiveness studies in various settings suggest that rapid-acting insulin analogues can be cost-effective, especially for type 1 diabetes. For type 2 diabetes, the cost–effectiveness is more variable. Survey data from different countries show significant variation in the prices of rapid-acting insulin analogues. While insulin analogues are often more expensive than human insulin, increased availability of biosimilars and efforts in price negotiations may help to lower costs in the future.
WHO guidelines
The 2018 WHO guidelines on second- and third-line medicines and type of insulin for the control of blood glucose levels in non-pregnant adults with diabetes include a strong recommendation (low-quality evidence) for the use of human insulin to control blood glucose levels in adults with type 1 diabetes and in adults with type 2 diabetes for whom insulin is indicated (8). The recommendation was strong because evidence of better effectiveness of insulin analogues was lacking, and human insulin had a better resource-use profile. The guidelines also include a weak recommendation to consider long-acting insulin analogues to control blood glucose levels in adults with type 1 or type 2 diabetes who have frequent severe hypoglycaemia with human insulin (moderate-quality evidence for severe hypoglycaemia) (8).
WHO guidelines for the pharmacological management of gestational diabetes or pre-existing diabetes in pregnant women are not currently available.
Availability
Rapid-acting insulin analogues, including insulin lispro, insulin aspart and insulin glulisine, have wide global regulatory approval. Biosimilar versions of insulin aspart and/or insulin lispro are available in some settings.
Other considerations
The Department of Noncommunicable Diseases, Rehabilitation and Disability reviewed and provided comments on the application. The technical department did not support the inclusion of rapid-acting insulin analogues on the Model Lists because of limitations in the evidence for benefits and the high costs of the medicines.
1. Global Burden of Disease database [online database]. Seattle, WA: Institute for Health Metrics and Evaluation; 2021 (https://vizhub.healthdata.org/gbd-results/).
2. Wang H, Li N, Chivese T, Werfalli M, Sun H, Yuen L et al. IDF Diabetes atlas: estimation of global and regional gestational diabetes mellitus prevalence for 2021 by International Association of Diabetes in Pregnancy Study Group's Criteria. Diabetes Res Clin Pract. 2022;183:109050 (https://doi.org/10.1016/j.diabres.2021.109050).
3. Fullerton B, Siebenhofer A, Jeitler K, Horvath K, Semlitsch T, Berghold A et al. Short-acting insulin analogues versus regular human insulin for adults with type 1 diabetes mellitus. Cochrane Database Syst Rev. 2016;2016(6):CD012161 (https://doi.org/10.1002/14651858.CD012161).
4. Nørgaard K, Sukumar N, Rafnsson SB, Saravanan P. Efficacy and safety of rapid-acting insulin analogs in special populations with type 1 diabetes or gestational diabetes: systematic review and meta-analysis. Diabetes Ther. 2018;9(3):891–917 (https://doi.org/10.1007/s13300-018-0411-7).
5. Melo KFS, Bahia LR, Pasinato B, Porfirio GJM, Martimbianco AL, Riera R et al. Short-acting insulin analogues versus regular human insulin on postprandial glucose and hypoglycemia in type 1 diabetes mellitus: a systematic review and meta-analysis. Diabetol Metab Syndr. 2019;11:2 (https://doi.org/10.1186/s13098-018-0397-3).
6. Fullerton B, Siebenhofer A, Jeitler K, Horvath K, Semlitsch T, Berghold A et al. Short-acting insulin analogues versus regular human insulin for adult, non-pregnant persons with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2018;12(12):CD013228 (https://doi.org/10.1002/14651858.CD013228).
7. O'Neill SM, Kenny LC, Khashan AS, West HM, Smyth RM, Kearney PM. Different insulin types and regimens for pregnant women with pre-existing diabetes. Cochrane Database Syst Rev. 2017;2(2):CD011880 (https://doi.org/10.1002/14651858.CD011880.pub2).
8. Guidelines on second-and third-line medicines and type of insulin for the control of blood glucose levels in non-pregnant adults with diabetes mellitus. Geneva: World Health Organization; 2018 (https://iris.who.int/handle/10665/272433). Licence: CC BY-NC-SA 3.0 IGO.
9. Hall JA, Summers KA, Obenchain RL. Cost and utilization comparisons among propensity score-matched insulin lispro and regular insulin users. J Manag Care Pharm. 2003;9(3):263–8 (https://doi.org/10.18553/jmcp.2003.9.3.263).
10. Chen K, Chang EY, Summers KH, Obenchain RL, Yu-Isenberg KS, Sun P. Comparison of costs and utilization between users of insulin lispro versus users of regular insulin in a managed care setting. J Manag Care Pharm. 2005;11(5):376–82 (https://doi.org/10.18553/jmcp.2005.11.5.376).
11. Davey P, Grainger D, MacMillan J, Rajan N, Aristides M, Dobson M. Economic evaluation of insulin lispro versus neutral (regular) insulin therapy using a willingness-to-pay approach. Pharmacoeconomics. 1998;13(3):347–58 (https://doi.org/10.2165/00019053-199813030-00009).
12. Kilburg A, Clouth J, Heinen-Kammerer T, Daniel D, Rychlik R. Modelling als Instrument der Hypothesengenerierung gesundheitsökonomischer Studien am Beispiel der antidiabetischen Behandlung mit Insulin lispro im Vergleich zur Normalinsulintherapie [Modelling as a tool for hypothesis generation in health economic studies using the example of antidiabetic treatment with insulin lispro compared to regular insulin therapy]. Gesundheitsökonomie & Qualitätsmanagement. 2002;7(02):96–100 (https://doi.org/10.1055/s-2002-25252).
13. Reviriego J, Gomis R, Marañés JP, Ricart W, Hudson P, Sacristán JA. Cost of severe hypoglycaemia in patients with type 1 diabetes in Spain and the cost–effectiveness of insulin lispro compared with regular human insulin in preventing severe hypoglycaemia. Int J Clin Pract. 2008;62(7):1026–32 (https://doi.org/10.1111/j.1742-1241.2008.01783.x).
14. Cameron CG, Bennett HA. Cost–effectiveness of insulin analogues for diabetes mellitus. Can Med Assoc J. 2009;180(4):400 (https://doi.org/10.1503/cmaj.081180).
15. Lloyd A, Townsend C, Munro V, Twena N, Nielsen S, Holman A. Cost–effectiveness of insulin aspart compared to human insulin in pregnant women with type 1 diabetes in the UK. Curr Med Res Opin. 2009;25(3):599–605 (https://doi.org/10.1185/03007990802668208).
16. Pratoomsoot C, Smith HT, Kalsekar A, Boye KS, Arellano J, Valentine WJ. An estimation of the long-term clinical and economic benefits of insulin lispro in type 1 diabetes in the UK. Diabet Med. 2009;26(8):803–14 (https://doi.org/10.1111/j.1464-5491.2009.02775.x).
17. Pollock RF, Valentine WJ, Pilgaard T, Nishimura H. The cost effectiveness of rapid-acting insulin aspart compared with human insulin in type 2 diabetes patients: an analysis from the Japanese third-party payer perspective. J Med Econ. 2011;14(1):36–46 (https://doi.org/10.3111/13696998.2010.541045).
18. Cazarim M, Rodrigues J, Cruz-Cazarim E, Ayres L, Pereira L. Cost–effectiveness of insulin analogs from the perspective of the Brazilian public health system. Braz J Pharm Sci. 2017;53(03) (https://doi.org/10.1590/s2175-97902017000300178).
19. Valentine WJ, Van Brunt K, Boye KS, Pollock RF. Treating type 1 diabetes mellitus with a rapid-acting analog insulin regimen vs. regular human insulin in Germany: a long-term cost-effectiveness evaluation. Appl Health Econ Health Policy. 2018;16(3):357–66 (https://doi.org/10.1007/s40258-018-0379-5).
20. Nosrati M, Ahmadi Fariman S, Saiyarsarai P, Nikfar S. Pharmacoeconomic evaluation of insulin aspart and glargine in type 1 and 2 diabetes mellitus in Iran. J Diabetes Metab Disord. 2023;22(1):817–25 (https://doi.org/10.1007/s40200-023-01209-1).
21. Ewen M, Joosse H-J, Beran D, Laing R. Insulin prices, availability and affordability in 13 low-income and middle-income countries. BMJ Glob Health. 2019;4(3):e001410 (https://doi.org/10.1136/bmjgh-2019-001410).
22. Wineinger NE, Zhang Y, Topol EJ. Trends in prices of popular brand-name prescription drugs in the United States. JAMA Network Open. 2019;2(5):e194791–e (https://doi.org/10.1001/jamanetworkopen.2019.4791).
23. Phulpagare M, Tiwari S, Hiray R. Cost excursion study of various insulin preparations available in India. J Clin Diagn Res. 2021;15(7):FC01–5 (https://doi.org/10.7860/JCDR/2021/48116.15107).
24. Saeed A, Lambojon K, Saeed H, Saleem Z, Anwer N, Aziz MM et al. Access to insulin products in Pakistan: a national scale cross-sectional survey on prices, availability, and affordability. Front Pharmacol. 2022;13:820621 (https://doi.org/10.3389/fphar.2022.820621).
25. Zarei L, Peymani P, Moradi N, Kheirandish M, Mirjalili M, Zare M. Affordability of medication therapy in diabetic patients: a scenario-based assessment in Iran’s health system context. Int J Health Policy Manag. 2022;11(4):443–52 (https://doi.org/10.34172/ijhpm.2020.152).
26. Barber MJ, Gotham D, Bygrave H, Cepuch C. Estimated sustainable cost-based prices for diabetes medicines. JAMA Network Open. 2024;7(3):e243474 (https://doi.org/10.1001/jamanetworkopen.2024.3474).
27. Bayat S, Perumal-Pillay VA, Suleman F. Availability and pricing of insulin and related diagnostics in South Africa. J Pharm Policy Pract. 2024;17(1):2372467 (https://doi.org/10.1080/20523211.2024.2372467).