Trial Outcomes & Findings for A Study to Compare a New Long-Acting Insulin (LY2605541) and Human Insulin NPH in Participants With Type 2 Diabetes (NCT NCT01790438)

Last Updated: 2018-05-03

Results Overview

Glycosylated hemoglobin A1 (HbA1c) is a test that measures a participant's average blood glucose level over a 2 to 3 month timeframe. Least Squares (LS) means were calculated by mixed model repeated measures (MMRM) using treatment, stratification factors (country, sulfonylureas/meglitinide use \[Yes/No\]), visit, treatment-by-visit interaction, and baseline HbA1c as the fixed effects.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

641 participants

Primary outcome timeframe

Baseline, 26 Weeks

Results posted on

2018-05-03

Participant Flow

Participant milestones

Participant milestones
Measure	LY2605541 Administered by subcutaneous (SC) injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on Fasting Blood Glucose (FBG). LY2605541 was given alone or in combination with up to 3 pre-study oral antihyperglycemic medications \[OAM(s)\] whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin isophane suspension (NPH) was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Overall Study STARTED	428	213
Overall Study Received at Least One Dose of Study Drug	427	212
Overall Study COMPLETED	393	202
Overall Study NOT COMPLETED	35	11

Reasons for withdrawal

Reasons for withdrawal
Measure	LY2605541 Administered by subcutaneous (SC) injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on Fasting Blood Glucose (FBG). LY2605541 was given alone or in combination with up to 3 pre-study oral antihyperglycemic medications \[OAM(s)\] whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin isophane suspension (NPH) was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Overall Study Adverse Event	3	2
Overall Study Death	4	0
Overall Study Lost to Follow-up	5	2
Overall Study Withdrawal by Subject	13	2
Overall Study Physician Decision	3	1
Overall Study Sponsor Decision	0	3
Overall Study Protocol Required Discontinuation	7	1

Baseline Characteristics

A Study to Compare a New Long-Acting Insulin (LY2605541) and Human Insulin NPH in Participants With Type 2 Diabetes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	LY2605541 n=428 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=213 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.	Total n=641 Participants Total of all reporting groups
Age, Continuous	58.86 years STANDARD_DEVIATION 9.76 • n=5 Participants	59.79 years STANDARD_DEVIATION 10.10 • n=7 Participants	59.17 years STANDARD_DEVIATION 9.87 • n=5 Participants
Sex: Female, Male Female	209 Participants n=5 Participants	107 Participants n=7 Participants	316 Participants n=5 Participants
Sex: Female, Male Male	219 Participants n=5 Participants	106 Participants n=7 Participants	325 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	148 Participants n=5 Participants	73 Participants n=7 Participants	221 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	195 Participants n=5 Participants	105 Participants n=7 Participants	300 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	85 Participants n=5 Participants	35 Participants n=7 Participants	120 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	53 Participants n=5 Participants	25 Participants n=7 Participants	78 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	27 Participants n=5 Participants	9 Participants n=7 Participants	36 Participants n=5 Participants
Race (NIH/OMB) White	345 Participants n=5 Participants	178 Participants n=7 Participants	523 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment United States	112 Participants n=5 Participants	60 Participants n=7 Participants	172 Participants n=5 Participants
Region of Enrollment Hungary	24 Participants n=5 Participants	11 Participants n=7 Participants	35 Participants n=5 Participants
Region of Enrollment Czechia	23 Participants n=5 Participants	12 Participants n=7 Participants	35 Participants n=5 Participants
Region of Enrollment Mexico	21 Participants n=5 Participants	11 Participants n=7 Participants	32 Participants n=5 Participants
Region of Enrollment Puerto Rico	46 Participants n=5 Participants	19 Participants n=7 Participants	65 Participants n=5 Participants
Region of Enrollment Canada	25 Participants n=5 Participants	13 Participants n=7 Participants	38 Participants n=5 Participants
Region of Enrollment Argentina	31 Participants n=5 Participants	14 Participants n=7 Participants	45 Participants n=5 Participants
Region of Enrollment Poland	37 Participants n=5 Participants	19 Participants n=7 Participants	56 Participants n=5 Participants
Region of Enrollment Spain	29 Participants n=5 Participants	16 Participants n=7 Participants	45 Participants n=5 Participants
Region of Enrollment Germany	30 Participants n=5 Participants	15 Participants n=7 Participants	45 Participants n=5 Participants
Region of Enrollment South Korea	50 Participants n=5 Participants	23 Participants n=7 Participants	73 Participants n=5 Participants
Body Mass Index (BMI)	30.80 kilograms/square meters (kg/m^2) STANDARD_DEVIATION 5.57 • n=5 Participants	31.04 kilograms/square meters (kg/m^2) STANDARD_DEVIATION 5.03 • n=7 Participants	30.88 kilograms/square meters (kg/m^2) STANDARD_DEVIATION 5.40 • n=5 Participants
Duration of Diabetes	10.87 years STANDARD_DEVIATION 6.46 • n=5 Participants	11.40 years STANDARD_DEVIATION 7.01 • n=7 Participants	11.05 years STANDARD_DEVIATION 6.65 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline, 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable HbA1c data.

Outcome measures

Outcome measures
Measure	LY2605541 n=420 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=212 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Change From Baseline to 26 Weeks in Hemoglobin A1c (HbA1c)	-1.73 percentage of HbA1c Standard Error 0.04	-1.36 percentage of HbA1c Standard Error 0.06

SECONDARY outcome

Timeframe: Baseline through 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable hypoglycemic data at baseline and with at least one post-baseline value.

Hypoglycemic episodes are defined as an event which is associated with reported signs and symptoms of hypoglycemia, and/or a documented blood glucose (BG) concentration of \<=70 milligram per deciliter (mg/dL) (3.9 millimoles per liter \[mmol/L\]). A nocturnal hypoglycemic event is defined as any total hypoglycemia event that occurred between bedtime and waking. Group mean rates of total and nocturnal hypoglycemia (per 30 days) are presented and were calculated from negative binomial regression models with treatment, baseline sulfonylurea/meglitinide use, baseline event rate of the corresponding hypoglycemia as covariates, log (exposure/30 days) as the offset in the model. Group Mean is estimated by taking the inverse link function on individual participant covariates first and then averages over all participants.

Outcome measures

Outcome measures
Measure	LY2605541 n=425 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=212 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
30-Day Adjusted Rate of Total and Nocturnal Hypoglycemic Events Total	1.46 episodes per participant per 30 days Standard Error 0.09	1.73 episodes per participant per 30 days Standard Error 0.13
30-Day Adjusted Rate of Total and Nocturnal Hypoglycemic Events Nocturnal	0.31 episodes per participant per 30 days Standard Error 0.04	0.61 episodes per participant per 30 days Standard Error 0.07

SECONDARY outcome

Timeframe: 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable HbA1c data.

Percentage of participants was calculated by dividing the number of participants reaching target HbA1c by the total number of participants analyzed, multiplied by 100.

Outcome measures

Outcome measures
Measure	LY2605541 n=420 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=212 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Percentage of Participants With HbA1c ≤6.5% and <7.0% HbA1c ≤6.5%	43.4 Percentage of Participants	24.1 Percentage of Participants
Percentage of Participants With HbA1c ≤6.5% and <7.0% HbA1c <7.0%	66.3 Percentage of Participants	44.7 Percentage of Participants

SECONDARY outcome

Timeframe: 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable FSG.

LS means were calculated from MMRM using treatment, stratification factors (country, sulfonylureas/meglitinide use \[Yes/No\]), baseline HbA1c strata \[≤8.5% or \>8.5%\]), visit, treatment-by-visit interaction, and baseline value of the response variable as the fixed effects.

Outcome measures

Outcome measures
Measure	LY2605541 n=422 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=212 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Fasting Serum Glucose (FSG) (by Laboratory)	112.61 milligrams per deciliter (mg/dL) Standard Error 1.56	118.60 milligrams per deciliter (mg/dL) Standard Error 2.20

SECONDARY outcome

Timeframe: 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable FBG data.

Outcome measures

Outcome measures
Measure	LY2605541 n=423 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=209 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Fasting Blood Glucose (FBG) (by Self Monitoring)	111.37 milligrams per deciliter (mg/dL) Standard Error 1.15	109.75 milligrams per deciliter (mg/dL) Standard Error 1.60

SECONDARY outcome

Timeframe: 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable blood glucose data.

6-point SMBG profiles were obtained on 3 nonconsecutive days in the week prior to Weeks 0, 4, 8, 12, 16, and 26. The SMBG measurements were performed while fasting (prior to the morning meal \[breakfast\]), prior to the midday meal (lunch), prior to the evening meal (dinner), at bedtime, at approximately 0300 hours, and the next day fasting (prior to the morning meal). LS means were calculated by MMRM using treatment, stratification factors (country, sulfonylureas/meglitinide use \[Yes/No\]), \], baseline HbA1c strata \[≤8.5% or \>8.5%\]), visit, treatment-by-visit interaction, and baseline SMBG at the same time point of the response variable as the fixed effects.

Outcome measures

Outcome measures
Measure	LY2605541 n=400 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=204 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
6-Point Self-Monitored Blood Glucose (SMBG) Pre-morning meal	111.22 mg/dL Standard Error 1.15	109.56 mg/dL Standard Error 1.61
6-Point Self-Monitored Blood Glucose (SMBG) Pre-midday meal	123.78 mg/dL Standard Error 1.75	133.77 mg/dL Standard Error 2.44
6-Point Self-Monitored Blood Glucose (SMBG) Pre-evening meal	130.90 mg/dL Standard Error 1.75	146.99 mg/dL Standard Error 2.41
6-Point Self-Monitored Blood Glucose (SMBG) Bedtime	144.14 mg/dL Standard Error 1.96	159.17 mg/dL Standard Error 2.72
6-Point Self-Monitored Blood Glucose (SMBG) 0300 hours	116.35 mg/dL Standard Error 1.55	117.66 mg/dL Standard Error 2.15
6-Point Self-Monitored Blood Glucose (SMBG) Pre-morning meal the next day	110.42 mg/dL Standard Error 1.18	109.03 mg/dL Standard Error 1.65

SECONDARY outcome

Timeframe: Baseline, 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable body weight data.

LS means were calculated by MMRM using treatment, stratification factors (country, sulfonylureas/meglitinide use \[Yes/No\]), baseline HbA1c strata \[≤8.5% or \>8.5%\]), visit, treatment-by-visit interaction, and baseline weight as the fixed effects.

Outcome measures

Outcome measures
Measure	LY2605541 n=419 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=212 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Change From Baseline to 26 Weeks in Body Weight	2.02 kilograms (kg) Standard Error 0.16	2.34 kilograms (kg) Standard Error 0.22

SECONDARY outcome

Timeframe: 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable HbA1c data.

HbA1c is a test that measures a participant's average blood glucose level over a 2 to 3 month timeframe. LS means were calculated by MMRM using treatment, stratification factors (country, sulfonylureas/meglitinide use \[Yes/No\]), visit, treatment-by-visit interaction, and baseline HbA1c as the fixed effects.

Outcome measures

Outcome measures
Measure	LY2605541 n=420 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=212 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
HbA1c	6.76 percentage of HbA1c Standard Error 0.04	7.12 percentage of HbA1c Standard Error 0.06

SECONDARY outcome

Timeframe: 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable insulin dose and body weight data.

LS means were calculated by MMRM using treatment, stratification factors (country, sulfonylureas/meglitinide use \[Yes/No\]), baseline HbA1c strata \[≤8.5% or \>8.5%\]), visit, and treatment-by-visit interaction as the fixed effects.

Outcome measures

Outcome measures
Measure	LY2605541 n=423 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=211 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Insulin Dose Per Kilogram (kg) of Body Weight	0.40 units per kilogram Standard Error 0.01	0.35 units per kilogram Standard Error 0.02

SECONDARY outcome

Timeframe: Baseline through 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable steady state data.

Steady-state was defined as the first local maximum dose (peak dose value) of LY2605541 or human insulin NPH within the window of -2 to +2 weeks. The median time to steady-state of basal insulin dose estimated from Kaplan-Meier analysis was summarized by treatment.

Outcome measures

Outcome measures
Measure	LY2605541 n=427 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=212 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Time to Steady-State (Stable Maximum Dose)	7.14 weeks Interval 6.57 to 8.14	5.86 weeks Interval 5.14 to 6.29

SECONDARY outcome

Timeframe: Baseline, 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable EQ-5D-3L data. Missing endpoints were imputed with the last observation carried forward (LOCF) method.

The EQ-5D-3L is a generic, multidimensional, health-related, quality-of-life instrument. The profile allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression using a three level scale 1-3 (no problem, some problems, and extreme problems). These combinations of attributes were converted into a weighted health-state Index Score according to the United States (US) population-based algorithm. The EQ-5D-3L US based index scores ranged from -0.11 to 1.0 where a score of 1.0 indicates perfect health. LS means were calculated from ANCOVA using treatment, stratification factor (country, baseline sulfonylurea sulfonylureas/meglitinide use \[Yes/No\], baseline HbA1c strata \[≤8.5% or \>8.5%\]) and baseline value of EQ-5D-3Las covariates.

Outcome measures

Outcome measures
Measure	LY2605541 n=397 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=204 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Change From Baseline to 26 Weeks in European Quality of Life - 5 Dimension 3 Levels (EQ-5D-3L) Index	0.02 units on a scale Standard Error 0.01	0.01 units on a scale Standard Error 0.01

SECONDARY outcome

Timeframe: 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable ITSQ data. Missing endpoints were imputed with the LOCF method.

ITSQ is a validated instrument containing 22 items that assess treatment satisfaction for participants with diabetes and on insulin. The questionnaire measures satisfaction from the following 5 domains: Inconvenience of Regimen, Lifestyle Flexibility, Glycemic Control, Hypoglycemic Control, Insulin Delivery Device. Data presented are the transformed score on a scale of 0-100, higher scores indicate better treatment satisfaction. LS means were calculated using analysis of variance (ANOVA) adjusting for treatment and stratification factors (country, baseline sulfonylureas/meglitinide use \[Yes/No\], baseline HbA1c \[≤8.5% or \>8.5%\]).

Outcome measures

Outcome measures
Measure	LY2605541 n=419 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=211 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Insulin Treatment Satisfaction Questionnaire (ITSQ) Score	85.04 units on a scale Standard Error 0.63	83.84 units on a scale Standard Error 0.89

SECONDARY outcome

Timeframe: Baseline, 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable LBSS data. Missing endpoints were imputed with the LOCF method.

Adult LBSS (also referenced as Hypoglycemia Fear Survey - II \[HFS-II\]) contains 33 items, with each item scored on a 5-point response scale: 0 (never) to 4 (always). Items are categorized in 2 domains: Behavior (or avoidance) with 15 items and Worry (or affect) with 18 items. Sum all the items to obtain a total score (range 0-132). Higher total scores reflect greater fear of hypoglycemia. LS means were calculated using analysis of covariance (ANCOVA) adjusting for treatment, stratification factor (country, baseline sulfonylureas/meglitinide use \[Yes/No\]), baseline HbA1c (≤8.5% or \>8.5%), and baseline value of LBSS.

Outcome measures

Outcome measures
Measure	LY2605541 n=400 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=206 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Change From Baseline to 26 Weeks in Adult Low Blood Sugar Survey (LBSS) Scores	0.53 units on a scale Standard Error 0.72	2.05 units on a scale Standard Error 1.01

SECONDARY outcome

Timeframe: Baseline, 26 Weeks; Baseline, End Of Study (EOS) (Up to 30 Weeks)

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable lipid data. Missing endpoints for End Of Study measures were imputed with the LOCF method.

Lipid profile includes total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides. LS means for post-baseline measures were calculated using MMRM with the fixed effects of stratification factors (baseline HbA1c \[≤8.5% and \>8.5%\], country, sulfonylureas/meglitinide use, and LDL-C \[\<100 mg/dL and ≥100 mg/dL\], except for the LDL-C outcome variable), visit, treatment, visit-by-treatment interaction, and baseline value of corresponding lipid outcome variable. LS means for End Of Study measures were calculated using ANCOVA adjusting for stratification factors (baseline HbA1c \[≤8.5% and \>8.5%\], country, sulfonylureas/meglitinide use, and LDL-C \[\<100 mg/dL and ≥100 mg/dL\]except for the LDL-C outcome variable), treatment, and baseline value of corresponding lipid outcome variable.

Outcome measures

Outcome measures
Measure	LY2605541 n=420 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=212 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Change From Baseline to 26 Weeks in Lipid Profile Total cholesterol, 26 Weeks	2.08 mg/dL Standard Error 1.42	2.86 mg/dL Standard Error 2.00
Change From Baseline to 26 Weeks in Lipid Profile Total cholesterol, End Of Study (Up to 30 Weeks)	-0.12 mg/dL Standard Error 1.36	2.94 mg/dL Standard Error 1.92
Change From Baseline to 26 Weeks in Lipid Profile HDL, 26 Weeks	-0.24 mg/dL Standard Error 0.31	0.41 mg/dL Standard Error 0.44
Change From Baseline to 26 Weeks in Lipid Profile HDL, End Of Study (Up to 30 Weeks)	0.53 mg/dL Standard Error 0.31	0.40 mg/dL Standard Error 0.44
Change From Baseline to 26 Weeks in Lipid Profile LDL, 26 Weeks	3.01 mg/dL Standard Error 1.24	5.90 mg/dL Standard Error 1.74
Change From Baseline to 26 Weeks in Lipid Profile LDL, End Of Study (Up to 30 Weeks)	2.54 mg/dL Standard Error 1.20	3.89 mg/dL Standard Error 1.69
Change From Baseline to 26 Weeks in Lipid Profile Triglycerides, 26 Weeks	-1.49 mg/dL Standard Error 4.62	-15.38 mg/dL Standard Error 6.49
Change From Baseline to 26 Weeks in Lipid Profile Triglycerides, End Of Study (Up to 30 Weeks)	-20.34 mg/dL Standard Error 4.79	-0.45 mg/dL Standard Error 6.74

SECONDARY outcome

Timeframe: Baseline to 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable anti-drug (LY2605541) antibodies (ADA) data.

The percentage of participants with a positive treatment-emergent anti-LY2605541 antibody response (TEAR) is summarized. TEAR was defined as change from baseline to postbaseline in the anti-LY2605541 antibody level either (1) from undetectable to detectable or (2) from detectable to the value with at least 130% relative increase from baseline. Percentage of participants was calculated by dividing the number of participants with TEAR anytime during the treatment period by the total number of participants analyzed, multiplied by 100.

Outcome measures

Outcome measures
Measure	LY2605541 n=422 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=212 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Percentage of Participants With Insulin Antibodies	19.7 percentage of participants	45.8 percentage of participants

SECONDARY outcome

Timeframe: 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable FBG data.

Glucose variability was assessed by between-day variability as measured by the standard deviation or the coefficient of variation of the FBG of the last 7 days prior to the visit using SMBG. LS means were calculated by MMRM using treatment, stratification factors (country, sulfonylureas/meglitinide use \[Yes/No\], baseline HbA1c strata \[≤8.5% or \>8.5%\]), visit, treatment-by-visit interaction, and baseline FBG variability as the fixed effects.

Outcome measures

Outcome measures
Measure	LY2605541 n=421 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=208 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Intra-Participant Variability in FBG by Standard Deviation	14.44 mg/dL Standard Deviation 0.50	19.07 mg/dL Standard Deviation 0.70

SECONDARY outcome

Timeframe: 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable FBG data.

Glucose variability was assessed by between-day variability as measured by the standard deviation or the coefficient of variation of the FBG of the last 7 days prior to the visit using SMBG.

Outcome measures

Outcome measures
Measure	LY2605541 n=421 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=208 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Intra-Participant Variability in FBG by the Coefficient of Variation	12.87 mg/dL Geometric Coefficient of Variation 0.40	17.05 mg/dL Geometric Coefficient of Variation 0.56

SECONDARY outcome

Timeframe: Baseline through 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable hypoglycemic data at baseline and with at least one post-baseline value.

Outcome measures

Outcome measures
Measure	LY2605541 n=425 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=212 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Percentage of Participants With Total and Nocturnal Hypoglycemic Events Total	76.7 percentage of participants	83.5 percentage of participants
Percentage of Participants With Total and Nocturnal Hypoglycemic Events Nocturnal	41.6 percentage of participants	67.5 percentage of participants

SECONDARY outcome

Timeframe: 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable HbA1c data and hypoglycemia data.

Outcome measures

Outcome measures
Measure	LY2605541 n=420 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=212 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Percentage of Participants With HbA1c <7.0% and Without Nocturnal Hypoglycemia	39.1 percentage of participants	12.6 percentage of participants

SECONDARY outcome

Timeframe: Baseline through 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH.

The percentage of participants with at least one treatment-emergent injection site reaction is presented. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.

Outcome measures

Outcome measures
Measure	LY2605541 n=427 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=212 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Percentage of Participants With Injection Site Reactions	0.9 percentage of participants	1.4 percentage of participants

SECONDARY outcome

Timeframe: Baseline through 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable hypoglycemic data at baseline and with at least one post-baseline value.

Hypoglycemic event are defined as an event which is associated with reported signs and symptoms of hypoglycemia, and/or a documented blood glucose (BG) concentration of \<=70 milligram per deciliter (mg/dL) (3.9 millimoles per liter \[mmol/L\]). A severe hypoglycemic event was defined as a hypoglycemic episode requiring assistance of another person to actively administer carbohydrates, glucagon, or other resuscitative actions. The hypoglycemia rate per 100 years during a defined period was calculated by the number of hypoglycemia events within the period divided by the number of days participant at risk within the period\*36525 days.

Outcome measures

Outcome measures
Measure	LY2605541 n=425 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=212 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Rate of Severe Hypoglycemic Events	1.00 events per 100 participant years Standard Deviation 0.71	0.00 events per 100 participant years Standard Deviation 0.00

SECONDARY outcome

Timeframe: Baseline through 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable hypoglycemic data at baseline and with at least one post-baseline value.

Hypoglycemic event are defined as an event which is associated with reported signs and symptoms of hypoglycemia, and/or a documented blood glucose (BG) concentration of \<=70 milligram per deciliter (mg/dL) (3.9 millimoles per liter \[mmol/L\]). A severe hypoglycemic event was defined as a hypoglycemic episode requiring assistance of another person to actively administer carbohydrates, glucagon, or other resuscitative actions. The percentage of participants with at least one severe hypoglycemia is presented. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.

Outcome measures

Outcome measures
Measure	LY2605541 n=425 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=212 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Percentage of Participants With Severe Hypoglycemic Events	0.5 percentage of participants	0.0 percentage of participants

SECONDARY outcome

Timeframe: Baseline, 26 Weeks

Population: Participants who received at least one dose of LY2605541 or human insulin NPH with evaluable EuroQol-5D-3L data.

The EQ-5D-3L is a generic, multidimensional, health-related, quality-of-life instrument. Overall health state score was self-reported using a visual analogue scale (VAS) marked on a scale of 0 to 100 with 0 representing worst imaginable health state and 100 representing best imaginable health state.

Outcome measures

Outcome measures
Measure	LY2605541 n=399 Participants Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=206 Participants Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Change From Baseline to 26 Weeks in European Quality of Life (EQ-5D-3L) - Visual Analog Scales (VAS) Scores	2.52 units on a scale Standard Deviation 0.68	1.41 units on a scale Standard Deviation 0.95

Adverse Events

LY2605541

Serious events: 28 serious events

Other events: 228 other events

Deaths: 0 deaths

Human Insulin NPH

Serious events: 9 serious events

Other events: 111 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-545-5979

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	LY2605541 n=427 participants at risk Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=212 participants at risk Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Cardiac disorders Acute myocardial infarction	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Cardiac disorders Angina unstable	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Cardiac disorders Atrial flutter	0.23% 1/427 • Number of events 2 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Cardiac disorders Atrioventricular block	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Cardiac disorders Cardiac arrest	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Cardiac disorders Cardiac failure	0.47% 2/427 • Number of events 3 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Cardiac disorders Cardiac failure congestive	0.47% 2/427 • Number of events 2 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Cardiac disorders Coronary artery insufficiency	0.00% 0/427 All participants who received at least one dose of study drug.	0.47% 1/212 • Number of events 3 All participants who received at least one dose of study drug.
Cardiac disorders Myocardial ischaemia	0.00% 0/427 All participants who received at least one dose of study drug.	0.47% 1/212 • Number of events 1 All participants who received at least one dose of study drug.
Gastrointestinal disorders Nausea	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Gastrointestinal disorders Pancreatitis	0.00% 0/427 All participants who received at least one dose of study drug.	0.47% 1/212 • Number of events 1 All participants who received at least one dose of study drug.
Gastrointestinal disorders Vomiting	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
General disorders Non-cardiac chest pain	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
General disorders Sudden death	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
General disorders Ulcer	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Hepatobiliary disorders Hepatic cirrhosis	0.23% 1/427 • Number of events 2 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Infections and infestations Abdominal wall abscess	0.00% 0/427 All participants who received at least one dose of study drug.	0.47% 1/212 • Number of events 1 All participants who received at least one dose of study drug.
Infections and infestations Bronchitis	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Infections and infestations Cellulitis	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Infections and infestations Gastrointestinal infection	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Infections and infestations Hepatitis C	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Infections and infestations Meningitis	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Infections and infestations Pneumonia	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Fall	0.00% 0/427 All participants who received at least one dose of study drug.	0.47% 1/212 • Number of events 1 All participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Radius fracture	0.00% 0/427 All participants who received at least one dose of study drug.	0.47% 1/212 • Number of events 1 All participants who received at least one dose of study drug.
Investigations Alanine aminotransferase increased	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.47% 1/212 • Number of events 2 All participants who received at least one dose of study drug.
Investigations Aspartate aminotransferase increased	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.47% 1/212 • Number of events 2 All participants who received at least one dose of study drug.
Metabolism and nutrition disorders Hypoglycaemia	0.47% 2/427 • Number of events 2 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Intervertebral disc disorder	0.23% 1/427 • Number of events 4 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Glioblastoma	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant peritoneal neoplasm	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-Hodgkin's lymphoma	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian neoplasm	0.00% 0/209 All participants who received at least one dose of study drug.	0.93% 1/107 • Number of events 1 All participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of skin	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Nervous system disorders Carotid artery stenosis	0.00% 0/427 All participants who received at least one dose of study drug.	0.47% 1/212 • Number of events 1 All participants who received at least one dose of study drug.
Nervous system disorders Syncope	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Psychiatric disorders Depression	0.47% 2/427 • Number of events 4 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Psychiatric disorders Suicidal ideation	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Renal and urinary disorders Calculus ureteric	0.47% 2/427 • Number of events 2 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Reproductive system and breast disorders Uterovaginal prolapse	0.00% 0/209 All participants who received at least one dose of study drug.	0.93% 1/107 • Number of events 2 All participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Sleep apnoea syndrome	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Skin and subcutaneous tissue disorders Psoriasis	0.23% 1/427 • Number of events 3 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.

Measure	LY2605541 n=427 participants at risk Administered by SC injection once daily in the morning or at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. LY2605541 was given alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks.	Human Insulin NPH n=212 participants at risk Administered by SC injection once daily at bedtime. Initial dose was 10 units and was adjusted weekly based on FBG. Human insulin NPH was used alone or in combination with up to 3 pre-study OAM(s) whose use was not excluded in combination with insulin. Treatment may have lasted up to 26 weeks. Some participants who were unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may have been asked to add a second injection prior to the morning meal.
Gastrointestinal disorders Abdominal pain upper	0.47% 2/427 • Number of events 2 All participants who received at least one dose of study drug.	1.4% 3/212 • Number of events 3 All participants who received at least one dose of study drug.
Gastrointestinal disorders Diarrhoea	3.0% 13/427 • Number of events 16 All participants who received at least one dose of study drug.	2.8% 6/212 • Number of events 9 All participants who received at least one dose of study drug.
Gastrointestinal disorders Dyspepsia	0.47% 2/427 • Number of events 2 All participants who received at least one dose of study drug.	2.4% 5/212 • Number of events 8 All participants who received at least one dose of study drug.
Gastrointestinal disorders Nausea	1.4% 6/427 • Number of events 6 All participants who received at least one dose of study drug.	1.4% 3/212 • Number of events 5 All participants who received at least one dose of study drug.
Gastrointestinal disorders Toothache	1.4% 6/427 • Number of events 6 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Gastrointestinal disorders Vomiting	1.2% 5/427 • Number of events 5 All participants who received at least one dose of study drug.	1.4% 3/212 • Number of events 3 All participants who received at least one dose of study drug.
General disorders Fatigue	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	2.4% 5/212 • Number of events 5 All participants who received at least one dose of study drug.
General disorders Oedema peripheral	2.6% 11/427 • Number of events 14 All participants who received at least one dose of study drug.	1.4% 3/212 • Number of events 3 All participants who received at least one dose of study drug.
Infections and infestations Bronchitis	1.9% 8/427 • Number of events 8 All participants who received at least one dose of study drug.	1.9% 4/212 • Number of events 4 All participants who received at least one dose of study drug.
Infections and infestations Herpes zoster	0.47% 2/427 • Number of events 2 All participants who received at least one dose of study drug.	1.4% 3/212 • Number of events 3 All participants who received at least one dose of study drug.
Infections and infestations Influenza	1.6% 7/427 • Number of events 8 All participants who received at least one dose of study drug.	3.3% 7/212 • Number of events 8 All participants who received at least one dose of study drug.
Infections and infestations Nasopharyngitis	6.8% 29/427 • Number of events 39 All participants who received at least one dose of study drug.	10.8% 23/212 • Number of events 34 All participants who received at least one dose of study drug.
Infections and infestations Sinusitis	1.4% 6/427 • Number of events 7 All participants who received at least one dose of study drug.	2.4% 5/212 • Number of events 7 All participants who received at least one dose of study drug.
Infections and infestations Tooth infection	1.2% 5/427 • Number of events 5 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Infections and infestations Upper respiratory tract infection	4.2% 18/427 • Number of events 23 All participants who received at least one dose of study drug.	2.4% 5/212 • Number of events 5 All participants who received at least one dose of study drug.
Infections and infestations Urinary tract infection	2.3% 10/427 • Number of events 14 All participants who received at least one dose of study drug.	1.9% 4/212 • Number of events 5 All participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Ligament sprain	1.2% 5/427 • Number of events 5 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Investigations Alanine aminotransferase increased	1.4% 6/427 • Number of events 8 All participants who received at least one dose of study drug.	0.94% 2/212 • Number of events 2 All participants who received at least one dose of study drug.
Investigations Weight increased	3.3% 14/427 • Number of events 15 All participants who received at least one dose of study drug.	2.4% 5/212 • Number of events 5 All participants who received at least one dose of study drug.
Metabolism and nutrition disorders Hypertriglyceridaemia	1.2% 5/427 • Number of events 5 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Arthralgia	0.70% 3/427 • Number of events 3 All participants who received at least one dose of study drug.	2.8% 6/212 • Number of events 7 All participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Back pain	3.7% 16/427 • Number of events 17 All participants who received at least one dose of study drug.	3.8% 8/212 • Number of events 10 All participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	1.4% 6/427 • Number of events 6 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Pain in extremity	2.6% 11/427 • Number of events 11 All participants who received at least one dose of study drug.	1.4% 3/212 • Number of events 6 All participants who received at least one dose of study drug.
Nervous system disorders Dizziness	0.94% 4/427 • Number of events 4 All participants who received at least one dose of study drug.	3.3% 7/212 • Number of events 8 All participants who received at least one dose of study drug.
Nervous system disorders Headache	5.4% 23/427 • Number of events 30 All participants who received at least one dose of study drug.	4.2% 9/212 • Number of events 17 All participants who received at least one dose of study drug.
Nervous system disorders Hypoaesthesia	1.4% 6/427 • Number of events 6 All participants who received at least one dose of study drug.	0.00% 0/212 All participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Cough	2.6% 11/427 • Number of events 12 All participants who received at least one dose of study drug.	5.2% 11/212 • Number of events 11 All participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	1.9% 8/427 • Number of events 8 All participants who received at least one dose of study drug.	1.9% 4/212 • Number of events 5 All participants who received at least one dose of study drug.
Skin and subcutaneous tissue disorders Lipohypertrophy	0.23% 1/427 • Number of events 1 All participants who received at least one dose of study drug.	1.4% 3/212 • Number of events 4 All participants who received at least one dose of study drug.
Skin and subcutaneous tissue disorders Rash	0.94% 4/427 • Number of events 4 All participants who received at least one dose of study drug.	1.4% 3/212 • Number of events 3 All participants who received at least one dose of study drug.
Vascular disorders Hypertension	1.4% 6/427 • Number of events 6 All participants who received at least one dose of study drug.	0.47% 1/212 • Number of events 1 All participants who received at least one dose of study drug.