In the AUTONOMY study, patients began mealtime insulin with one injection at breakfast1
Is your patient a candidate for self-titration with Humalog?
Overview of the AUTONOMY study
In the AUTONOMY study, mealtime insulin lispro therapy by selftitration was effectively initiated with a single breakfast injection and adjusted in adult patients with type 2 diabetes on basal insulin and OADs using either the Q1D or Q3D algorithm.2
The patients in the AUTONOMY trial2:
- Had uncontrolled A1C
- Were on ≥ 20 units of basal insulin once daily and were on 1 or more oral antidiabetes drugs (OADs)
- Were aged 18-85
- Had type 2 diabetes
- Had BMI <45kg/m2
Select Important Safety Information
Humalog and Insulin Lispro Injection are contraindicated during episodes of hypoglycemia and in patients who are hypersensitive to these insulins or any of their excipients.
For more information, contact your Lilly Sales Representative or call The Lilly Answers Center at 1-800-LillyRx (1-800-545-5979).
Q1D algorithm2
Using the Q1D algorithm, patients self-titrated every day based on premeal or bedtime blood glucose (BG) readings, respectively, from the previous day. For example, when adjusting the prebreakfast dose, patients used their prelunch readings from the previous day. The premeal target BG was 85-114 mg/dL. If the patient had a BG reading of ≥115 mg/dL, the patient increased the lispro dose by 1 unit/day until the target was reached. For a BG reading of 56-84 mg/dL, the dose was decreased by 1 unit, and for a reading of <56 mg/dL, the dose was decreased by 2 units.
Q3D algorithm2
Using the Q3D algorithm, patients self-titrated every 3 days based on the median BG readings from the 3 days before.2 Accordingly, to adjust the prebreakfast dose, the patient used the median prelunch BG reading from the past 3 days. If the median reading was 85-114 mg/dL, there was no change in lispro dose. For median 115-144 mg/dL, the patient increased the dose by 2 units. For median ≥145 mg/dL, the dose was increased by 4 units. For median 56-84 mg/dL, the dose was decreased by 2 units. For median <56 mg/dL, the dose was decreased by 4 units.
Select Important Safety Information
Never share a Humalog or Insulin Lispro Injection prefilled pen, cartridge, reusable pen compatible with Lilly 3 mL cartridges, or syringe between patients as it poses a risk for transmission of blood-borne pathogens.
AUTONOMY study design2
The AUTONOMY study was a 24-week, multicenter, randomized, open-label, parallel trial of adult patients (N=1106) with type 2 diabetes inadequately controlled on basal insulin, conducted in primary care and endocrinology settings, to compare 2 patient self-titration algorithms for initiating and adjusting prandial insulin lispro.
AUTONOMY consisted of 2 identical studies (Study A and Study B) using the same protocol to compare the primary outcome of change in A1C from baseline after 24 weeks between a daily (Q1D) or 3-day (Q3D) algorithm. Interventions consisted of adding lispro sequentially by 1, 2, or 3 mealtime injections to their baseline glargine. Initial lispro dose began at breakfast.
The primary and secondary objectives were evaluated for the overall population and subjects ≥65 years old.
Select Important Safety Information
Changes in insulin regimen (e.g. insulin strength, manufacturer, type, injection site, or method of administration) may affect glycemic control and predispose patients to hypoglycemia and hyperglycemia. Make changes cautiously with increased frequency of blood glucose monitoring.
In the AUTONOMY study, mealtime insulin lispro therapy by self-titration was effectively initiated with a single breakfast injection and adjusted in adult patients with type 2 diabetes on basal insulin and OADs using either the Q1D or Q3D algorithm2.
- Injections using the AUTONOMY algorithm were administered using Humalog U-100 KwikPen3
- Were not required to count carbohydrates to adjust titration2
- Under healthcare provider direction, patients recorded their BG readings, and then self-adjusted their prandial insulin based on their readings either every day or every three days2
Starting dose2
- The initial breakfast mealtime dose was equivalent to 10% of the total daily glargine dose
Patients assessed and adjusted their own mealtime insulin2
- Following the Q1D algorithm, patients adjusted the breakfast dose daily based on the previous day’s prelunch BG reading
- When prelunch BG readings were consistently in the 85-114 mg/dL range, no further breakfast dose adjustments were required
Select Important Safety Information
Severe hypoglycemia may be life threatening and can cause seizures or death. Hypoglycemia is the most common adverse effect of Humalog and Insulin Lispro Injection therapy. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia.
For Patients Who Used the Q1D Algorithm at 24 Weeks2,4:
Additional doses were added at healthcare providers (HCPs) discretion2,5
- Once the optimal breakfast injection dose was reached and prelunch blood glucose readings were within the 85-114 mg/dL range the HCP determined whether or not a lunch dose was needed. If additional control was required (pre-dinner blood glucose readings >/115 mg/dL), patients made adjustments using the same algorithm that they used for the breakfast dose.
-
For each meal, the base unit lispro dose was equivalent to5:
- 10% of the total daily glargine dose at lunch
- 5% of the total daily glargine dose at dinner
- Lunch and dinner doses were titrated daily using the Q1D algorithm until the respective BG targets were reached
- Lunch dose adjustments were based on the previous day’s predinner BG reading
- Dinner dose adjustments were based on the previous day’s bedtime BG reading
- In the AUTONOMY study 61.2% of patients using the Humalog KwikPen required only 1 or 2 daily injections of mealtime insulin at endpoint2-4
Select Important Safety Information
Instruct patients to always check the insulin label before each injection to avoid medication errors. Do NOT transfer Humalog U-200 from the Humalog KwikPen to a syringe as overdose and severe hypoglycemia can occur.
Efficacy with self-titration algorithm
Patients experienced a 1.0% mean reduction in A1C from baseline (8.3%) to endpoint with the Q1D self-titration algorithm2
All efficacy analyses were based upon the full analysis set (subjects in the all-randomized population who took at least one dose of insulin lispro). A limitation of this study was the exclusion of subjects with BMIs ≥45 kg/m2.
Change in A1C in the 24-week AUTONOMY study of Q1D and Q3D algorithms, of Study A (N=528) and Study B (N=578). Data were reported as least square mean (LSM) ± SE of the mean and 95% CI from a mixed effect model for repeated measures (MMRM) that included baseline A1C, strata, treatment algorithm, visit, and treatment algorithm by visit.
Similar results were seen with the Q3D arm of the study: change in A1c from baseline (8.3%) at week 24 was -0.96% for Study A and -0.92% for Study B.
Select Important Safety Information
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with Humalog and Insulin Lispro Injection. If hypersensitivity reactions occur, discontinue the insulin and treat per standard of care until signs and symptoms resolve.
Using the Q1D algorithm, almost half of the patients achieved an A1C of ≤ 7.0% at 24 weeks.2
Subjects Who Achieved A1C ≤7.0% at 24 Weeks2,6,7
All efficacy analyses were based upon the full analysis set (subjects in the all-randomized population who took at least one dose of insulin lispro). At week 24, Study A=520; Study B=560.
The percentages of subjects achieving A1C targets at the end of the study (last observation carried forward [LOCF]) were analyzed using a logistic regression model with terms for treatment algorithm and strata.
Following the Q1D algorithm, 12 patients in Study A and 16 patients in Study B had an HbA1c ≤7.0% at baseline.
Following the Q3D algorithm, 13 patients in Study A and 13 patients in Study B had an HbA1c ≤7.0% at baseline.
Subjects ≥65 Years of Age Who Achieved A1C ≤7.0% at 24 Weeks2,6,7
All efficacy analyses were based upon the full analysis set (subjects in the all-randomized population who took at least one dose of insulin lispro). At week 24, Study A=520; Study B=560.
The percentages of subjects achieving A1C targets at the end of the study (last observation carried forward [LOCF]) were analyzed using a logistic regression model with terms for treatment algorithm and strata.
Following the Q1D algorithm, 12 patients in Study A and 16 patients in Study B had an HbA1c ≤7.0% at baseline.
Following the Q3D algorithm, 13 patients in Study A and 13 patients in Study B had an HbA1c ≤7.0% at baseline.
Data are reported as mean (SE) at week 24. N= number of patients in specified treatment and subgroup category. Values are based on patients with non-missing HbA1c at baseline and at week 24 in the specified treatment and subgroup category. P-values for the 2-way interaction (treatment by subgroup) are from the MMRM model: response=baseline + strata + treatment + visit + treatment by visit + subgroup + treatment by subgroup. The primary and secondary objectives were evaluated for the overall population and subjects ≥65 years old.
Select Important Safety Information
Hypokalemia may be life threatening. Insulins, including Humalog and Insulin Lispro Injection, 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).
Hypoglycemia
Overall Hypoglycemia Rates and Incidence in the AUTONOMY Study8
Type of Hypoglycemia (rate and incidence)
|
Study A: Q1D (n=268)
|
Study B: Q1D (n=289)
|
---|---|---|
Total hypoglycemia incidence (n [%]) | Study A: Q1D (n=268): 231 (86.2) | Study B: Q1D (n=289): 238 (82.4) |
Total hypoglycemia rate per 30 days | Study A: Q1D (n=268): 3.15 ± 0.23 | Study B: Q1D (n=289): 3.18 ± 0.26 |
Symptomatic hypoglycemia incidence (n [%]) | Study A: Q1D (n=268): 194 (72.4) | Study B: Q1D (n=289): 205 (70.9) |
Symptomatic hypoglycemia rate per 30 days | Study A: Q1D (n=268): 1.72 ± 0.16 | Study B: Q1D (n=289): 1.50 ± 0.15 |
Nocturnal hypoglycemia incidence (n [%]) | Study A: Q1D (n=268): 169 (63.1) | Study B: Q1D (n=289): 156 (54.0) |
Nocturnal hypoglycemia rate per 30 days | Study A: Q1D (n=268): 0.71 ± 0.07 | Study B: Q1D (n=289): 0.59 ± 0.07 |
Severe hypoglycemia incidence (n [%]) | Study A: Q1D (n=268): 5 (1.9) | Study B: Q1D (n=289): 7 (2.4) |
Severe hypoglycemia rate per 30 days | Study A: Q1D (n=268): 0.00 ± 0.03 | Study B: Q1D (n=289): 0.01 ± 0.09 |
Data are n (%), negative binomial mean (NBM) ± SE.
Incidence is reported as the number of patients with at least 1 hypoglycemic episode. All safety outcomes were assessed in the all-randomized population (all patients who entered the study, completed the glargine optimization lead-in period (if applicable), and were randomized to 1 of the 2 treatment arms). The rate of total, documented asymptomatic, and nocturnal hypoglycemia per 30 days during the treatment phase was analyzed using LOCF.8 Due to low occurence of severe hypoglycemia, mean ± SD and only Wilcoxon test p-values are presented.
Similar rates and incidence of hypoglycemia were observed in Q1D and Q3D algorithms in both studies (A and B).
A hypoglycemic episode was defined as any time a patient felt that he or she was experiencing a sign or symptom associated with hypoglycemia, or had a blood glucose level of ≤70 mg/dL even if it was not associated with signs, symptoms, or treatment.
Documented symptomatic hypoglycemia was defined as an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration ≤70 mg/dL.
A nocturnal hypoglycemic episode was defined as any time a patient felt that he or she was experiencing a sign or symptom associated with hypoglycemia, or had a blood glucose level of ≤70 mg/dL even if it was not associated with signs or symptoms and occurred after bedtime and prior to the first meal upon waking (eg, breakfast).
A severe hypoglycemic episode was defined as any time a patient required assistance of another person for treatment and that was accompanied by neurologic (cognitive) impairment.8
The rate of total, nocturnal, documented symptomatic, and documented asymptomatic hypoglycemia per 30 days (or per year) was analyzed at each visit using a negative binomial model with terms for treatment algorithm, HbA1c stratum, visit, treatment algorithm by visit, sulfonylurea/meglitinide use - yes or no, and the logorithm of the exposure time (in days) as an offset variable and compound symmetry as variance-covariance structure both at endpoint and overall using a negative binomial model with terms for treatment algorithm, HbA1c stratum, sufonylurea/meglitinide use - yes or no, logorithm of the exposure time (in days) as an offset variable. The rate per subject per 30 days (or per year) calculated between 2 visits was defined as the total number of epidodes between the visits divided by the actual number of days between the visits and then multiplied by 30 days (or 365.25 days). In addition, a Wilcoxon rank sum test was conducted as a sensitivity analysis. If the model still did not converge, sulfonylurea/meglitinide use and HbA1c stratum could have been deleted from the model.
Select Important Safety Information
Severe hypoglycemia may be life threatening and can cause seizures or death. Hypoglycemia is the most common adverse effect of Humalog and Insulin Lispro Injection therapy. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia.
Hypoglycemia Rates and Incidence in Patients Aged 65 Years and Older in the AUTONOMY Study8
Type of Hypoglycemia (rate and incidence)
|
Study A: Q1D (n=66)
|
Study B: Q1D (n=56)
|
---|---|---|
Total hypoglycemia incidence (n [%]) | Study A: Q1D (n=66): 60 (90.9) | Study B: Q1D (n=56): 51 (91.1) |
Total hypoglycemia rate per 30 days | Study A: Q1D (n=66): 3.42 ± 0.45 | Study B: Q1D (n=56): 4.22 ± 0.68 |
Symptomatic hypoglycemia incidence (n [%]) | Study A: Q1D (n=66): 52 (78.8) | Study B: Q1D (n=56): 39 (69.6) |
Symptomatic hypoglycemia rate per 30 days | Study A: Q1D (n=66): 1.71 ± 0.29 | Study B: Q1D (n=56): 1.85 ± 0.42 |
Nocturnal hypoglycemia incidence (n [%]) | Study A: Q1D (n=66): 45 (68.2) | Study B: Q1D (n=56): 42 (75.0) |
Nocturnal hypoglycemia rate per 30 days | Study A: Q1D (n=66): 0.72 ± 0.12 | Study B: Q1D (n=56): 0.99 ± 0.20 |
Severe hypoglycemia incidence (n [%]) | Study A: Q1D (n=66): 3 (4.5) | Study B: Q1D (n=56): 1 (1.8) |
Severe hypoglycemia rate per 30 days | Study A: Q1D (n=66): 0.01 ± 0.04 | Study B: Q1D (n=56): 0.00 ± 0.03 |
Data are n (%), NBM ± SE.
Incidence is reported as the number of patients with at least one hypoglycemic episode. All safety outcomes were assessed in the all-randomized population (all patients who entered the study, completed the glargine optimization lead-in period (if applicable), and were randomized to 1 of the 2 treatment arms). The rate of total, documented symptomatic, and nocturnal hypoglycemia per 30 days during the treatment phase was analyzed using LOCF. Due to low occurence of severe hypoglycemia, mean ± SD and only Wilcoxon test p-values are presented.8
Similar rates and incidence of hypoglycemia were observed in Q1D and Q3D algorithms in both studies (A and B) in patients ≥65 years of age.
Select Important Safety Information
Fluid retention and heart failure can occur with concomitant use of TZDs and Humalog or Insulin Lispro Injection. Observe patients for signs and symptoms of heart failure and consider discontinuation to dose reduction of the PPAR-gamma agonist.
Weight Gain
Subjects Weight Change From Baseline at 24 Weeks
Weight (kg) Change From Baseline (LSM ± SE) at 24 Weeks2
- Patients following the AUTONOMY Q1D algorithm had mean weight gains of approximately 2.15 to 2.47 kg (4.7 to 5.4 lb) in Study A and Study B, respectively, during the study period2,9
- In Study A, Q3D participants gained slightly more weight (approximately 1.8 lb) than Q1D participants9
Data were reported as LSM ± SE of the mean based upon an MMRM that included baseline weight, strata, treatment algorithm, visit, and treatment algorithm by visit.
INDICATIONS
Humalog and Insulin Lispro Injection are rapid-acting insulin analogs indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. Humalog Mix75/25 and Humalog Mix50/50, and Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 are mixtures of intermediate-acting and rapid-acting human insulin analogs indicated to improve glycemic control in patients with diabetes mellitus.
Limitations of Use: The proportions of rapid-acting and intermediate-acting insulins in Humalog Mix75/25 and Humalog Mix50/50, and Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 are fixed and do not allow for basal versus prandial dose adjustments.