Tirzepatide as an Add-on for Participants with Inadequate Glycemic Control Using Basal Insulin: Pooled Subgroup Analysis of SURPASS-5 and -6

Abstract

Introduction

This study aimed to assess the efficacy and hypoglycemia safety of tirzepatide as an add-on to basal insulin in people with inadequate glycemic control, across subgroups of baseline age, type 2 diabetes (T2D) duration, HbA1c, and basal insulin dosage using pooled data from the SURPASS-5 and -6 studies.

Methods

This exploratory post hoc analysis compared data from 1072 participants treated with tirzepatide as an add-on to basal insulin in SURPASS-5 and SURPASS-6. In SURPASS-5, tirzepatide was compared against placebo, while in SURPASS-6, it was compared with insulin lispro. Insulins were titrated to the target in both trials. Subgroups were divided by baseline HbA1c (≤ 8.5% and > 8.5%), age (< 65 years and ≥ 65 years), duration of T2D (< 10 years and ≥ 10 years), and insulin glargine dose (< 50 IU/day and ≥ 50 IU/day).

Results

At the primary endpoint, tirzepatide added to basal insulin glargine was associated with significant reductions in HbA1c, fasting serum glucose, and insulin glargine dose across all subgroups (P < 0.001), with no significant heterogeneity (all interaction P values > 0.1). Clinically significant hypoglycemia incidence rates were highest in younger participants with a baseline HbA1c above 8.5% and duration of T2D ≥ 10 years.

Conclusions

In this study, tirzepatide combined with basal insulin glargine was associated with reductions in HbA1c, fasting serum glucose, and insulin glargine dose from baseline, with a low incidence of hypoglycemia, regardless of baseline age, HbA1c, duration of T2D, or basal insulin dose.

Trial Registration

Trials were registered at ClinicalTrials.gov under the identifiers NCT04039503 (SURPASS-5) and NCT04537923 (SURPASS-6).

Key Summary Points

Why carry out this study?

Basal insulins are a common treatment option for people with T2D, and analyzing subgroup effects in a T2D trial of basal insulin users is important, as outcomes can vary significantly.

This analysis evaluated the glycemic control, body weight reduction, and hypoglycemia risk when tirzepatide was used as an add-on to basal insulin in various subgroups, identified according to HbA1c, age, duration of T2D, and basal insulin dose at baseline.

What was learned from the study?

Tirzepatide added to basal insulin glargine was associated with significant reductions in HbA1c, fasting serum glucose, and insulin glargine dose across all subgroups, with no significant heterogeneity.

Tirzepatide was associated with significant body weight reduction from baseline at all doses in all subgroups, with a low incidence of hypoglycemia, regardless of baseline age, HbA1c, duration of T2D, or basal insulin dose.

Introduction

Basal insulins are a common treatment option for people with type 2 diabetes (T2D). Additional treatments, such as prandial insulin, glucagon-like peptide 1 (GLP-1) receptor agonists, or dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 (GIP/GLP-1) receptor agonists, may be used in combination with basal insulin to improve glycemic control and reduce body weight. Tirzepatide is a once-weekly GIP/GLP-1 receptor agonist. Tirzepatide is indicated as an adjunct to diet and exercise for the treatment of adults with T2D, chronic weight management, and obstructive sleep apnea. Tirzepatide has been associated with improved blood glucose control through enhanced β-cell function, increased insulin sensitivity, and weight reduction [1–3].

The efficacy and safety of tirzepatide as an add-on to basal insulin have been established in two global phase 3 studies, SURPASS-5 (compared with placebo) and SURPASS-6 (compared with basal-bolus insulin therapy). In both studies, tirzepatide demonstrated clinically meaningful and superior improvements in HbA1c (− 2.11% to − 2.40%) compared with baseline and proportion of participants reaching glycemic targets of < 7% (58% to 89.6%), ≤ 6.5% (56% to 85.9%), and < 5.7% (18% to 49.6%) at primary endpoint. Furthermore, tirzepatide treatment resulted in clinically meaningful weight reduction in both trials. The rates of clinically significant hypoglycemia (blood glucose < 54 mg/dL or severe hypoglycemia) were comparable to placebo and significantly lower compared with basal-bolus therapy. However, these studies were not designed to demonstrate the sparing effect of tirzepatide; up to 19% of participants in SURPASS-6 discontinued insulin by week 52.

A broad population with varied baseline glycemic control, basal insulin use, age, and duration of diabetes participated in the SURPASS-5 and -6 trials. Analyzing subgroup effects in a T2D clinical trial of basal insulin users is important, as empirical evidence shows that outcomes can vary significantly. For example, older patients (≥ 65 years) may experience different glycemic responses and hypoglycemia risks compared with younger patients. Longer diabetes duration (> 10 years) has been associated with attenuated β-cell function and differing treatment efficacy. Similarly, baseline HbA1c strata have been shown in multiple trials to predict the magnitude of HbA1c reduction and cardiovascular risk modification, underscoring that averaged overall results may obscure clinically relevant heterogeneity in benefit and safety. Patients on basal insulin initiating tirzepatide can adjust the dose of basal insulin to optimize efficacy while minimizing risk of potential hypoglycemia and to individualize treatment. Data across key subgroups can help prescribers make informed decisions. Since SURPASS-5 and -6 enrolled similar patient populations, pooling their data increases subgroup sample sizes and allows for more robust efficacy and safety assessments. This analysis evaluated the glycemic control, body weight reduction, and hypoglycemia risk when tirzepatide was used as an add-on to basal insulin in various subgroups identified according to HbA1c (8.5% cutoff), age (65 years old cutoff), duration of T2D (10 years cutoff), and basal insulin dose at baseline (50 IU/day cutoff).

Methods

Study Design

This is a post hoc subgroup analysis from two global randomized controlled phase 3 clinical trials for tirzepatide, SURPASS-5 and -6. Participants with T2D and inadequate glycemic control using basal insulin with or without metformin were enrolled. Detailed trial design and results were previously published [4, 5].

SURPASS-5 had a primary endpoint of 40 weeks and included a placebo comparator. SURPASS-6 had a 52-week endpoint and included an active comparator, prandial insulin lispro. In both studies, participants were on a background basal insulin therapy of insulin glargine (100 IU/mL).

In both trials, tirzepatide treatment was initiated at 2.5 mg once weekly, and the dose was increased by 2.5 mg every 4 weeks until the assigned dose (5 mg, 10 mg, or 15 mg) was reached. In SURPASS-5, participants were enrolled on insulin glargine, while in SURPASS-6, participants entered the study on different basal insulin regimens and were switched to insulin glargine for up to 10 weeks to stabilize therapy. At randomization, the insulin glargine dose was reduced to lower hypoglycemia risk and safely introduce study treatment: by 20% in SURPASS-5 participants having a pre-trial HbA1c ≤ 8%, or by 30% in all SURPASS-6 participants. In both trials, participants titrated the dose of insulin glargine to a target fasting blood glucose (less than 100 mg/dL in SURPASS-5 and < 125 mg/dL in SURPASS-6).

Clinically significant hypoglycemia was defined as any event with a blood glucose level less than 54 mg/dL, or severe hypoglycemic events (defined as events resulting in cognitive impairment requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions).

Here, data from the SURPASS-5 and -6 populations were pooled because of their similar population characteristics. Only data from the tirzepatide groups from baseline to week 40 were included. Comparator groups were not pooled because they differed between the two studies. Subgroups were divided as follows: baseline HbA1c ≤ 8.5% (N = 530; 49.5%) and HbA1c > 8.5% (N = 541; 50.5%); age < 65 years (N = 702; 65.5%) and age ≥ 65 years (N = 370; 34.5%); duration of T2D < 10 years (N = 350, 32.6%) and duration of T2D ≥ 10 years (N = 722, 67.4%); and insulin glargine dose < 50 IU/day (N = 677, 63.2%) and insulin glargine dose ≥ 50 IU/day (N = 394, 36.8%). Considering the mean baseline HbA1c in SURPASS-5 and SURPASS-6, a subgroup analysis with an HbA1c cutoff of 8.5% was justified to have equal numbers of patients in each subgroup.

The studies were designed to follow the guidelines outlined in the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. All protocols obtained approval by a local ethical review board ahead of study start. Participants provided signed informed consent, and local ethical review boards approved all protocols.

Statistical Analyses

Efficacy and safety analyses were performed on all randomly assigned participants who received at least one dose of the study drug. Additionally, the efficacy analysis set (EAS) excluded data collected after initiation of rescue medication or after discontinuation of the study drug. The safety analysis set (SAS) included all available data from participants in the safety population regardless of adherence to the study drug or initiation of rescue antihyperglycemic medication. Mixed model for repeated measures (MMRM) assessed changes from baseline at the endpoint in HbA1c, fasting serum glucose, insulin glargine dose, and body weight in the EAS. The model adjusted for study identifier, baseline, treatment, time, and treatment-by-time interaction. No missing value imputation was conducted. Safety analysis provided descriptive statistics on the incidence of clinically significant hypoglycemia (severe hypoglycemia or blood glucose < 3 mmol/L [< 54 mg/dL]). All statistical analyses were performed using SAS Version 9.4 (SAS Institute), and P values < 0.05 were considered statistically significant.

Results

Baseline Characteristics

Table 1 summarizes the pooled baseline characteristics stratified by subgroup defined by HbA1c, age, T2D duration, or insulin daily dose. The HbA1c ≤ 8.5% subgroup had an average HbA1c of 7.8% and fasting serum glucose (FSG) of 140.8 mg/dL; the HbA1c > 8.5% subgroup had an average HbA1c of 9.4% and FSG of 178.0 mg/dL. The age < 65 years subgroup had an average age of 53.9 years and T2D duration of 12.3 years; the age ≥ 65 years subgroup had an average age of 69.6 years and T2D duration of 15.8 years. The T2D duration < 10 years subgroup had an average T2D duration of 6.0 years and an age of 55.8 years; the T2D duration ≥ 10 years subgroup had an average T2D duration of 17.2 years and an age of 61.1 years. The insulin dose < 50 IU/day subgroup had an average median daily insulin glargine dose of 34 IU and a body weight of 89.0 kg; the insulin dose ≥ 50 IU/day subgroup had an average median daily insulin glargine dose of 63 IU and a body weight of 98.0 kg. All other baseline characteristics were comparable between subgroups.

Table 1.

Baseline demographics

	Pooled tirzepatide 5 mg, 10 mg, and 15 mg groups
	HbA1c		Age		T2D duration		Insulin dose
	≤ 8.5% N = 530	> 8.5% N = 541	< 65 years N = 702	≥ 65 years N = 370	< 10 years N = 350	≥ 10 years N = 722	< 50 IU/day N = 677	≥ 50 IU/day N = 394
Age, years ± SD	60.2 ± 9.9	58.5 ± 9.8	53.9 ± 7.5	69.6 ± 3.9	55.8 ± 10.6	61.1 ± 9.0	60.2 ± 9.9	57.8 ± 9.6
Female, n (%)	273 (51.5)	309 (57.1)	383 (54.6)	200 (54.1)	171 (48.9)	412 (57.1)	377 (55.7)	206 (52.3)
Body weight, kg ± SD	93.2 ± 20.3	91.4 ± 19.0	93.9 ± 20.1	89.2 ± 18.5	96.6 ± 20.5	90.2 ± 19.0	89.0 ± 19.2	98.0 ± 19.2
BMI, kg/m2 ± SD	33.4 ± 5.7	33.3 ± 5.5	33.7 ± 5.7	32.8 ± 5.3	34.4 ± 5.7	32.8 ± 5.5	32.4 ± 5.6	34.9 ± 5.2
T2D duration, years ± SD	13.5 ± 7.3	13.6 ± 7.2	12.3 ± 6.7	15.8 ± 7.6	6.0 ± 2.4	17.2 ± 5.9	13.4 ± 7.5	13.8 ± 6.9
HbA1c, % ± SD	7.8 ± 0.5	9.4 ± 0.7	8.7 ± 1.0	8.5 ± 1.0	8.6 ± 1.0	8.7 ± 1.0	8.5 ± 0.9	8.9 ± 1.0
FSG, mg/dL ± SD	140.8 ± 43.6	178.0 ± 59.5	161.8 ± 56.3	155.2 ± 53.4	163.9 ± 51.9	157.4 ± 56.9	156.5 ± 52.2	164.8 ± 60.4
iGlar median dose, IU/day (range)	40 (17–152)	45 (12–268)	44 (16–268)	40 (12–164)	40 (20–106)	43 (12–268)	34 (12–49)	63 (50–268)

Baseline demographics by subgroup for tirzepatide (pooled)

BMI body mass index, FSG fasting serum glucose, HbA1c glycated hemoglobin, iGlar insulin glargine, IU international unit, N number of participants per subgroup, SD standard deviation

Glycemic Control by Subgroup

At week 40, all doses of tirzepatide were associated with significantly reduced HbA1c, FSG, and insulin glargine dose from baseline in all subgroups (P < 0.001), with all p values for interactions by subgroups being > 0.1, as seen in Fig. 1. We observed that participants in higher baseline HbA1c categories had numerically greater reductions from baseline, ranging from 2.7 ± 0.08% (5 mg) to 3.1 ± 0.08% (15 mg). Comparatively, participants with a baseline HbA1c value less than or equal to 8.5% experienced a reduction in HbA1c between 1.7 ± 0.06% (5 mg) and 2.0 ± 0.06% (15 mg) from baseline.

Fig. 1.

Glycemic efficacy and insulin dose change of tirzepatide by dose. Change from baseline at endpoint in a HbA1c, b FSG, and c iGlar dose. Data are presented as least squares mean. Error bars represent standard error of mean *P < 0.001. FSG fasting serum glucose, HbA1c glycated hemoglobin, iGlar insulin glargine, IU international unit, n number of participants per subgroup, SD standard deviation

Reduction in FSG was consistent across all subgroups. However, tirzepatide-treated participants with a baseline HbA1c above 8.5% tended to experience a larger reduction in FSG: up to 70.5 ± 2.90 mg/dL in the 15 mg treatment arm, compared with a 40.6 ± 2.16 mg/dL reduction in the 15 mg treatment arm for those with baseline HbA1c ≤ 8.5%. There was no notable difference in trends across the age, T2D duration, and insulin dose subgroups.

Across all subgroups, there was no heterogeneity in the insulin glargine dose, which decreased with tirzepatide treatment. This reduction was dose-dependent, being greater in the higher tirzepatide dose treatment groups. There was a trend towards greater dose reduction among participants with a baseline dose at or above 50 IU/day, ranging from 16.5 ± 1.91 IU/day (5 mg) to 28.7 ± 1.92 IU/day (15 mg). In comparison, those with a daily insulin glargine dose below 50 IU/day experienced dose reductions from 3.0 ± 1.20 IU/day (5 mg) to 8.9 ± 1.23 IU/day (15 mg).

Body Weight Change of Tirzepatide-Treated Participants by Subgroup

As seen in Fig. 2, tirzepatide was associated with significantly reduced body weight from baseline at all doses in all subgroups at the endpoint (P < 0.001). Across all subgroups, participants experienced weight reduction in a tirzepatide dose-dependent manner. The smallest body weight reduction across all subgroups and tirzepatide doses (− 5.2 ± 0.43 kg) occurred in the 5 mg treatment arm, in those with a baseline HbA1 above 8.5%. The greatest reduction (− 12.0 ± 0.55 kg) occurred in the 15 mg treatment arm in those with a baseline HbA1c ≤ 8.5%. No significant heterogeneity was observed across baseline age, T2D duration, HbA1c, and insulin dosage subgroups (all interaction P values > 0.2). Nonetheless, participants with lower baseline HbA1c values appeared to experience greater weight reduction than those with higher baseline HbA1c values.

Fig. 2.

Body weight change of tirzepatide by dose. Change from baseline at endpoint in body weight. Data are presented as least squares mean. Error bars represent standard error of mean *P < 0.001. HbA1c glycated hemoglobin, IU international unit, n number of participants per subgroup

Clinically Significant or Severe Hypoglycemia Events

The incidence and rate of clinically significant hypoglycemia are presented in Table 2. Overall, across all tirzepatide doses, participants with baseline HbA1c > 8.5% and a T2D duration of ≥ 10 years tended to have numerically higher incidence and rates of clinically significant hypoglycemia than those with HbA1c ≤ 8.5% or T2D duration < 10 years, respectively. Participants with a baseline insulin dose of ≥ 50 IU/day tended to have numerically lower incidence of clinically significant hypoglycemia than those with a baseline insulin dose < 50 IU/day for pooled tirzepatide treatment.

Table 2.

Incidence and rate of clinically significant hypoglycemia events

Treatment group		HbA1c		Age		T2D duration		Insulin dose
		≤ 8.5% N = 530	> 8.5% N = 541	< 65 years N = 702	≥ 65 years N = 370	< 10 years N = 350	≥ 10 years N = 722	< 50 IU/day N = 677	≥ 50 IU/day N = 394
Tirzepatide 5 mg	Incidence, n (%)	19 (11.0)	27 (14.5)	26 (11.0)	20 (16.3)	8 (7.1)	38 (15.5)	23 (10.1)	23 (17.4)
	Rate per year	0.27	1.03	0.82	0.35	0.20	0.87	0.65	0.69
Tirzepatide 10 mg	Incidence, n (%)	20 (11.4)	23 (12.8)	33 (15.1)	10 (7.3)	14 (11.8)	29 (12.2)	22 (9.7)	21 (16.3)
	Rate per year	0.34	0.81	0.43	0.81	0.37	0.67	0.65	0.43
Tirzepatide 15 mg	Incidence, n (%)	18 (9.9)	22 (12.6)	28 (11.3)	12 (11.0)	12 (10.2)	28 (11.8)	21 (9.5)	19 (14.3)
	Rate per year	0.32	0.33	0.31	0.37	0.25	0.36	0.23	0.48
Tirzepatide, pooled	Incidence, n (%)	57 (10.8)	72 (13.3)	87 (12.4)	42 (11.4)	34 (9.7)	95 (13.2)	66 (9.7)	63 (16.0)
	Rate per year	0.31	0.72	0.52	0.51	0.27	0.63	0.51	0.53

Hypoglycemia incidences from baseline to week 40 by subgroup

Incidence consists of clinically significant hypoglycemia events per subgroup, defined as any event with a blood glucose level less than 54 mg/dL, or severe hypoglycemic events (defined as events resulting in cognitive impairment requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions). Rate per year was the aggregate rate per year of hypoglycemia events per subgroup

HbA1c glycated hemoglobin, IU international unit, n number of participants per subgroup

Participants with a baseline HbA1c ≤ 8.5% or a disease duration < 10 years had the lowest aggregated rate of hypoglycemia per year for pooled tirzepatide treatment (Table 2, defined as the number of hypoglycemic episodes divided by the total exposure). Conversely, participants with a baseline HbA1c > 8.5% tended to have a higher aggregated rate of hypoglycemia per year. A total of six severe hypoglycemia events were reported, three events in SURPASS-5 [4] and three events in SURPASS-6 [5].

Discussion

In this pooled analysis of SURPASS-5 and -6, tirzepatide added to daily glargine 100 IU/mL in adults with T2D was associated with significant reductions in HbA1c, FSG, and insulin dose regardless of baseline HbA1c, age, duration of disease, or baseline insulin dosage, with no significant heterogeneity observed within these subgroups.

The efficacy and safety of a therapy can differ based on patient- and disease-specific factors, including age, body mass index (BMI), race, HbA1c, and disease duration [6–9]. In the present analysis, there was a trend toward greater reductions in HbA1c and FSG in the subgroup with worse glycemic control, as indicated by a higher baseline HbA1c value. Along with tirzepatide, long-acting GLP-1 receptor agonists, including dulaglutide [10] and semaglutide [11], added to basal insulin have been reported to achieve greater HbA1c reductions in participants with a higher baseline HbA1c. This is in line with a previous analysis that suggested baseline HbA1c was a key predictor of glycemic efficacy [12].

However, while the trends were the same, tirzepatide appears to be associated with greater reductions in HbA1c and weight than both dulaglutide and semaglutide when used in conjunction with basal insulin. Dulaglutide added to insulin glargine resulted in a reduction in HbA1c of 1.4% from baseline [13], while semaglutide added to insulin glargine lowered HbA1c by 1.4% to 1.8% [14], compared with the 1.7% to 3.1% HbA1c reduction observed with tirzepatide added to glargine in the current analysis. Similarly, tirzepatide showed greater body weight reduction across subgroups (up to 12.0 kg) compared with dulaglutide (2.4 kg) and semaglutide (up to 6.4 kg) in previously published analyses [13, 14].

In the present analysis, participants aged 65 years or older or those with T2D duration ≥ 10 years demonstrated reductions in HbA1c similar to those observed in the younger population with shorter disease duration. Similarly, in the SUSTAIN trials, semaglutide [11] demonstrated similar efficacy and safety, irrespective of baseline age and T2D duration.

Hypoglycemia events were predominantly observed in participants with T2D duration ≥ 10 years and those with HbA1c > 8.5%. The occurrence of hypoglycemia is generally anticipated in individuals with longer diabetes duration; however, this difference in hypoglycemic incidence based on baseline HbA1c was not observed with dulaglutide in either the AWARD-4 or -9 studies [10], and was opposite to the results observed with semaglutide in SUSTAIN-7 [14]. The protocol requirements in SURPASS-5 for mandatory insulin reduction in participants with pre-trial HbA1c ≤ 8% likely mitigated hypoglycemia risk in the lower-HbA1c subgroup. The elevated hypoglycemia rate in those with a higher baseline HbA1c underscores the importance of proactive basal insulin dose reduction when initiating tirzepatide in this population. It can be difficult to compare hypoglycemia incidence rates with other treatments because of differences in hypoglycemic cutoffs and study endpoints. Still, tirzepatide treatment across subgroups was associated with comparable incidence rates to other therapies (dulaglutide + iGlar [13], dulaglutide [15], and semaglutide [14]).

Overall, the present analysis provides insight into the effects of combining two potent glucose-lowering medications (tirzepatide and basal insulin) in specific subgroups, providing valuable information for clinicians to tailor treatment strategies. Additionally, this analysis further supports the glycemic and weight-reduction efficacy, as well as the safety of tirzepatide, regardless of an individual’s age or diabetes duration.

Limitations

These results should be interpreted with several limitations in mind. This was an exploratory post hoc pooled analysis that was not pre-specified and therefore was not designed to support causal inference. In addition, imbalanced and small sample sizes across subgroups may have limited the statistical power to detect heterogeneity of treatment effects. Consequently, the findings should be interpreted descriptively rather than inferentially. Because SURPASS-5 and -6 enrolled different populations, combining them may also inadvertently introduce bias. Hence, interpretation based on a pooled analysis of these trials must be considered with caution and not generalized beyond the patient population represented by the inclusion/exclusion criteria. Additionally, as the comparator groups between the two studies were neither uniform nor pooled, conclusions reflect the efficacy and safety of tirzepatide relative to baseline within subgroups. Finally, the time point selected for the analysis was 40 weeks, which may not adequately reflect the long-term effects of tirzepatide.

Conclusions

Tirzepatide added to basal insulin in adults with T2D was associated with significant, clinically meaningful glycemic and weight reductions, regardless of baseline HbA1c, age, disease duration, or insulin dosage. These data aim to assist clinicians in adopting a personalized treatment strategy for participants with T2D, offering further understanding of incorporating tirzepatide therapy for those already on insulin treatment.

Author Contributions

Harpreet S Bajaj was involved in the interpretation of data for the work and the critical revision of the work for important intellectual content. Liana K Billings was involved in the interpretation of data, drafting, and critical revision of the work for important intellectual content. Palash Sharma was involved with the acquisition, analysis, and interpretation of data for the work, along with critical revision of the work for important intellectual content. Joshua A Levine was involved with the analysis and interpretation of data for the work, along with critical revision of the work for important intellectual content. Angel Rodriguez was involved in the design of the work, acquisition and interpretation of data, and critical revision of the work for important intellectual content. Hiren Patel was involved with the conception and design of the work, interpretation of data, drafting, and critical revision of the work for important intellectual content.

Funding

This study and the journal’s rapid service fee was funded by Eli Lilly and Company.

Data Availability

Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, except for pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the USA and European Union and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data have been made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data-sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report and blank or annotated case report forms, will be provided in a secure data-sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.

Declarations

Conflict of Interest

Angel Rodriguez, Hiren Patel, and Palash Sharma are employees and shareholders of Eli Lilly and Company; Joshua A Levine is an employee and shareholder of Pfizer Inc., shareholder of Eli Lilly and Company, and was an employee of Eli Lilly and Company at the time of manuscript development. Harpreet S Bajaj has received trial fees paid to his institution by Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Ionis Pharmaceuticals, Kowa Pharmaceuticals Co. Ltd., Novartis, Novo Nordisk and Pfizer Inc.; Liana K Billings has received consulting honoraria from Bayer Pharmaceuticals, Eli Lilly and Company, Endogenex, Novo Nordisk, Pfizer Inc., Sanofi and Xeris Pharmaceuticals.

Ethical Approval

The studies were designed to follow the guidelines outlined in the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. All protocols obtained approval by a local ethical review board ahead of study start. Participants provided signed informed consent, and local ethical review boards approved all protocols.