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 adult 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
Lyumjev: A rapid-acting human insulin analog indicated to improve glycemic control in adults and children 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. 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.
Warnings and Precautions
Never Share a Lyumjev or Humalog Prefilled Pen, Cartridge, Syringe, or Humalog Reusable Pen Compatible with Lilly 3 mL Cartridges Between Patients, even if the needle is changed. Patients using Lyumjev or Humalog vials must never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.
Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen: Changes in insulin strength, manufacturer, type, injection site, or method of administration may affect glycemic control and predispose to hypoglycemia or hyperglycemia. Use caution and close medical supervision when making any changes in insulin regimen and increase the frequency of blood glucose monitoring. Due to reports of hyperglycemia and hypoglycemia, advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor blood glucose. For patients with type 2 diabetes, dosage adjustments of concomitant antidiabetic products may be needed.
Hypoglycemia: Severe hypoglycemia may be life threatening, may lead to unconsciousness, and can cause seizures or death. Hypoglycemia is the most common adverse reaction of Lyumjev and Humalog. Monitor blood glucose and increase monitoring frequency with changes to insulin dosage, coadministered medications, meal pattern, or physical activity; in patients with renal or hepatic impairment; and in patients with hypoglycemia unawareness.
Hypoglycemia Due to Medication Errors: Instruct patients to always check the insulin label before each injection to avoid medication errors. Do not transfer Lyumjev U-200 from the Lyumjev KwikPen® to a syringe and do not transfer Humalog U-200 from the Humalog KwikPen® to a syringe as overdose and severe hypoglycemia can occur.
Hypokalemia: Hypokalemia may be life threatening. Insulins, including Lyumjev and Humalog, 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 (e.g., patients using potassium-lowering medications or medications sensitive to serum potassium concentrations).
Hypersensitivity Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with Lyumjev and Humalog. If hypersensitivity reactions occur, discontinue the use of Lyumjev or Humalog and treat per standard of care until signs and symptoms resolve.
Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists: Thiazolidinediones (TZDs), which are PPAR-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin, including Lyumjev and Humalog. This may lead to or exacerbate heart failure. Observe patients for signs and symptoms of heart failure and consider discontinuation or dose reduction of the PPAR-gamma agonist.
Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Malfunction: Pump or infusion set malfunctions and insulin degradation can lead to a rapid onset of hyperglycemia and ketoacidosis. Prompt identification is necessary. Patients using subcutaneous insulin infusion pumps must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure.
Adverse reactions associated with Lyumjev and Humalog include hypoglycemia, hypokalemia, allergic reactions, injection- or infusion-site reactions, lipodystrophy, localized cutaneous amyloidosis, pruritus, rash, weight gain, and peripheral edema.
Some medications may alter glucose metabolism, insulin requirements, and the risk for hypoglycemia or hyperglycemia. Signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs. Particularly close monitoring may be required.
Lyumjev-treated pediatric patients reported a higher incidence of subcutaneous injection site-related reactions compared to Lyumjev-treated adults. It is expected that Lyumjev-treated pediatric patients who receive continuous subcutaneous insulin infusion (CSII) are more likely to have infusion site-related adverse reactions than those who receive subcutaneous injections. Monitor injection and infusion sites closely when initiating therapy with Lyumjev in pediatric patients. If persistent injection or infusion site reactions occur, discontinue Lyumjev and initiate therapy with an alternative insulin.
UR HI HCP ISI 14OCT2022