Lyumjev achieved its primary endpoint of A1C noninferiority vs Humalog® (insulin lispro injection) 100 units/mL in 2 treat-to-target trials1
Primary endpoint: A1C noninferiority1-3
The PRONTO phase 3 trials for Lyumjev studied nearly 1900 patients with type 1 and type 2 diabetes.1
Noninferiority was demonstrated for mealtime Lyumjev by change in A1C vs Humalog at 26 weeks.1-3
A separate postmeal arm of the study included 329 adults with type 1 diabetes.
In treat-to-target trials in diabetes, each treatment arm aims to achieve the same ranges of glycemic control to allow for comparison of clinical measures, including postmeal glucose levels.2-4
Indication for Lyumjev: Lyumjev is indicated to improve glycemic control in adults with diabetes mellitus.
Select Important Safety Information for Lyumjev
Hypokalemia may be life threatening. Insulins, including Lyumjev, cause a shift in potassium from the extracellular to intracellular space possibly leading to hypokalemia, which, if untreated, may result in respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia (eg, patients using potassium-lowering medications or medications sensitive to serum potassium concentrations).
PRONTO studies evaluated A1C noninferiority in adults with diabetes
PRONTO study design: Two 26-week, randomized, treat-to-target, multicenter, parallel studies including 1222 adults with type 1 diabetes (T1D) and 673 with type 2 diabetes (T2D). Mealtime insulins used in these trials were 100 U/mL. The primary objective was noninferiority (noninferiority margin [NIM]=0.4% for A1C) of mealtime Lyumjev to Humalog in A1C change from baseline to week 26. Key secondary objectives (with multiplicity adjustment) were statistical superiority of Lyumjev to Humalog at week 26 in 1-hour and 2-hour postprandial glucose (PPG) excursions, and noninferiority (NIM=0.4% for A1C) of the change in A1C of postmeal Lyumjev vs mealtime Humalog (PRONTO-T1D).1,5,6
Type 1 design: Inclusion criteria included T1D on multiple daily injections. Following an 8-week lead-in, patients were randomized in a 4:4:3 ratio to mealtime Lyumjev, mealtime Humalog, or postmeal Lyumjev. Mealtime arms were double-blind and administered 0-2 minutes before the start of a meal. Postmeal arm was open-label and administered 20 minutes after the start of a meal. Basal insulin was insulin glargine 100 U/mL once or twice daily or insulin degludec 100 U/mL once daily.1,5
Type 2 design: Inclusion criteria included basal insulin + ≥1 bolus or ≥2 premixed insulin injections daily and up to 3 oral antidiabetic medications (OAMs). Following an 8-week lead-in, patients were randomized in a 1:1 ratio to mealtime Lyumjev or mealtime Humalog. This was a double-blind study with doses administered 0-2 minutes before the start of a meal. Basal insulin was insulin glargine 100 U/mL once or twice daily or insulin degludec 100 U/mL or 200 U/mL once daily. OAMs during study: Metformin and/or SGLT2 inhibitor could be continued.1,6
Superior 1- and 2-hour PPG reductions with Lyumjev vs Humalog2,7,8
Lyumjev had superior reductions in postmeal glucose excursions at both 1 and 2 hours vs Humalog.2,7,8
PPG Excursions After a Standardized Meal Test* in Type 1 Diabetes at Week 26
PPG Excursions After a Standardized Meal Test* in T2D at Week 26
The clinical significance of PPG excursions has not been established.
Select Important Safety Information for Lyumjev
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with Lyumjev. If hypersensitivity reactions occur, discontinue the insulin and treat per standard of care until signs and symptoms resolve.
PRONTO-T1D CGM Substudy: Efficacy Results
Time in target range based on week 26 AGP9
Ambulatory Glucose Profiles (Median and Percentile) of Lyumjev and Humalog by Treatment Group 0-4 Hours Postmeal at Week 269
Limitation: This study had a small sample size and was limited to patients with T1D. Presented TIR data is not generalizable to patients with T2D. Caution should be exercised in the interpretation of TIR in this study, as it was not multiplicity adjusted. Appropriateness of TIR as a clinical efficacy endpoint has not been determined. See full study design below .
Time-in-range data for Lyumjev and Humalog9
Secondary Endpoint: Time in Range* (Minutes) in Patients with T1D9
Nighttime TIR (Midnight–6 AM) for Lyumjev (n=85): 187 minutes; for Humalog (n=81): 188 minutes. The difference per period was 1 minute.9
CGM substudy design: A substudy of 269 adult patients included in PRONTO-T1D. A blinded CGM, Dexcom G4®, was used for up to 14 days during 2 periods of time (prior to randomization and the 26-week primary endpoint). The primary outcome measurement was the iAUC0–2h after the start of breakfast at week 26. Secondary outcome measures included comparison of glucose thresholds prespecified for calculation of various time-in-range (TIR) parameters in this study as measured by CGM data.9,10
Select Important Safety Information For Lyumjev
Fluid retention and heart failure can occur with concomitant use of TZDs and Lyumjev. Observe patients for signs and symptoms of heart failure and consider discontinuation or dose reduction of the PPAR-gamma agonist.
Primary endpoint (iAUC0-2h after breakfast at week 26 in mg*hour/dL): 27.1 with Lyumjev (n=53) and 55.3 with Humalog (n=53)9,10
- Lyumjev [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC.
- Klaff LJ, Cao D, Dellva MA, et al. Ultra rapid lispro (URLi) improves postprandial glucose (PPG) control vs. Humalog (lispro) in T1D: PRONTO-T1D Study. Diabetes. 2019;68(suppl 1). doi:10.2337/db19-144-OR.
- Blevins T, Zhang Q, Frias JP, Jinnouchi H, Chang AM. Ultra rapid lispro (URLi) improves postprandial glucose (PPG) control vs. Humalog (lispro) in patients with type 2 diabetes (T2D): PRONTO-T2D. Diabetes. 2019;68(suppl 1). doi:10.2337/db19-145-OR.
- Garber AJ. Treat-to-target trials: uses, interpretation and review of concepts. Diabetes Obes Metab. 2014;16(3):193-205. doi:10.1111/dom.12129.
- Data on File, Lilly USA, LLC, DOF-UR-US-0002.
- Data on File, Lilly USA, LLC, DOF-UR-US-0003.
- Data on File, Lilly USA, LLC, DOF-UR-US-0021.
- Data on File, Lilly USA, LLC, DOF-UR-US-0022.
- Malecki MT, Cao D, Liu R, et al. Ultra-rapid lispro improves postprandial glucose control and time in range in type 1 diabetes compared to lispro: PRONTO-T1D continuous glucose monitoring substudy. Diabetes Technol Ther. 2020;22(11):853-860. doi:10.1089/dia.2020.0129.
- Data on File, Lilly USA, LLC, DOF-UR-US-0007.