Tirzepatide vs Insulin Lispro Added to Basal Insulin in Type 2 Diabetes: The SURPASS-6 Randomized Clinical Trial
Open accessAbstract
Importance: Tirzepatide is a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist used for the treatment of type 2 diabetes. Efficacy and safety of adding tirzepatide vs prandial insulin to treatment in patients with inadequate glycemic control with basal insulin have not been described. Objective: To assess the efficacy and safety of tirzepatide vs insulin lispro as an adjunctive therapy to insulin glargine. Design, Setting, and Participants: This open-label, phase 3b clinical trial was conducted at 135 sites in 15 countries (participants enrolled from October 19, 2020, to November 1, 2022) in 1428 adults with type 2 diabetes taking basal insulin. Interventions: Participants were randomized (in a 1:1:1:3 ratio) to receive once-weekly subcutaneous injections of tirzepatide (5 mg [n = 243], 10 mg [n = 238], or 15 mg [n = 236]) or prandial thrice-daily insulin lispro (n = 708). Main Outcomes and Measures: Outcomes included noninferiority of tirzepatide (pooled cohort) vs insulin lispro, both in addition to insulin glargine, in HbA 1c change from baseline at week 52 (noninferiority margin, 0.3%). Key secondary end points included change in body weight and percentage of participants achieving hemoglobin A 1c (HbA 1c) target of less than 7.0%. Results: Among 1428 randomized participants (824 [57.7%] women; mean [SD] age, 58.8 [9.7] years; mean [SD] HbA 1c, 8.8% [1.0%]), 1304 (91.3%) completed the trial. At week 52, estimated mean change from baseline in HbA 1c with tirzepatide (pooled cohort) was −2.1% vs −1.1% with insulin lispro, resulting in mean HbA 1c levels of 6.7% vs 7.7% (estimated treatment difference, −0.98% [95% CI, −1.17% to −0.79%]; P < .001); results met noninferiority criteria and statistical superiority was achieved. Estimated mean change from baseline in body weight was −9.0 kg with tirzepatide and 3.2 kg with insulin lispro (estimated treatment difference, −12.2 kg [95% CI, −13.4 to −10.9]). The percentage of participants reaching HbA 1c less than 7.0% was 68% (483 of 716) with tirzepatide and 36% (256 of 708) with insulin lispro (odds ratio, 4.2 [95% CI, 3.2-5.5]). The most common adverse events with tirzepatide were mild to moderate gastrointestinal symptoms (nausea: 14%-26%; diarrhea: 11%-15%; vomiting: 5%-13%). Hypoglycemia event rates (blood glucose level <54 mg/dL or severe hypoglycemia) were 0.4 events per patient-year with tirzepatide (pooled) and 4.4 events per patient-year with insulin lispro. Conclusions and Relevance: In people with inadequately controlled type 2 diabetes treated with basal insulin, weekly tirzepatide compared with prandial insulin as an additional treatment with insulin glargine demonstrated reductions in HbA 1c and body weight with less hypoglycemia. Trial Registration: ClinicalTrials.gov Identifier: NCT04537923
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In a Phase 2 substudy in subjects with MASLD, retatrutide significantly decreased liver fat, with a reduction of up to 86% over a 48-week period.
“Finally, in a Phase 2 substudy in subjects with MASLD, retatrutide significantly decreased liver fat; displaying a substantial reduction of up to 86% over a 48 week period167 (Table 2),”
From Transforming obesity: The advancement of multi-receptor drugs (2024) · cites this paper as [167]
The trial description identifies this as a phase 3b study of tirzepatide versus insulin lispro in adults with type 2 diabetes, with outcomes assessed at week 52—not a phase 2 retatrutide substudy in people with MASLD. The Discussion mentions liver-fat reduction only as a reported effect of tirzepatide from another study; it does not report an 86% reduction over 48 weeks. (LLM, conf=0.89)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredRecently, several large-scale randomized controlled trials specifically targeting patients with obesity but without diabetes have been published.
“Recently, several large-scale randomized controlled trials (RCTs) specifically targeting patients with obesity but without diabetes have been published [24,25,26,27,28].”
From The Efficacy and Safety of Tirzepatide in Patients with Diabetes and/or Obesity: Systematic Review and Meta-Analysis of Randomized Clinical Trials (2025) · cites this paper as [28]
The Methods identify this as a randomized phase 3b trial, but the Participants section states that eligible adults had type 2 diabetes inadequately controlled with basal insulin. It therefore cannot serve as an example of an RCT specifically targeting patients with obesity but without diabetes. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIn the overall population, 107 participants experienced an episode of severe hypoglycaemia, with 30 of the cases occurring in a single trial arm wherein participants were randomised to prandial insulin.
“in the overall population, 107 participants experienced an episode of severe hypoglycaemia, with 30 of the cases occurring in a single trial arm wherein participants were randomised to prandial insulin [46]”
From Subcutaneously administered tirzepatide vs semaglutide for adults with type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials (2024) · cites this paper as [46]
The Adverse Events and Tolerability section reports severe hypoglycemia in 30 insulin lispro-treated participants, supporting the prandial-insulin arm count. It also reports 3 tirzepatide-treated participants, making 33 participants overall, not 107. The reported event counts total 106, which are distinct from participant counts; no page number is available in our copy. (LLM, conf=0.94)
Experimental — accuracy not yet measuredThe efficacy of tirzepatide (5, 10 and 15 mg once weekly subcutaneous injection) was assessed in the SURPASS trial programme which showed greater glucose-lowering and weight-lowering effects than semaglutide and other GLP-1 receptor agonists.
“The efficacy of tirzepatide (5, 10 and 15 mg once weekly subcutaneous injection: Mounjaro ) was assessed in the SURPASS trial programme which showed greater glucose-lowering and weight-lowering effects than semaglutide and other GLP-1RAs [57-62].”
From Recent advances in peptide-based therapies for obesity and type 2 diabetes (2024) · cites this paper as [62]
Mean WL ranged from −11.7 kg to −12.9 kg with tirzepatide 15 mg at 52 weeks.
“Mean WL ranged from −11.7 kg to −12.9 kg with tirzepatide 15 mg at 52 weeks and up to 43% of people with T2D achieved ≥ 15% WL, even if tirzepatide was not combined with a lifestyle intervention at SURPASS programme.”
Tirzepatide has been approved for T2D management at doses of 5, 10 and 15 mg once-weekly based on findings from phase 3 SURPASS program.
“Tirzepatide, a unimolecular dual agonist of GLP-1 and GIP receptors, has been approved for T2D management at the doses of 5, 10 and 15 mg once-weekly based on findings from the phase 3 SURPASS program [40–45].”
In SURPASS clinical trials, tirzepatide resulted in HbA1c reduction up to 2.6%.
“In these clinical trials, tirzepatide resulted in HbA1c reduction up to 2.6%, with 70–94% of participants achieving HbA1c ≤ 6.5% with tirzepatide 15 mg (Table 2, Figure 3).”
70-94% of participants achieved HbA1c ≤6.5% with tirzepatide 15 mg.
“In these clinical trials, tirzepatide resulted in HbA1c reduction up to 2.6%, with 70–94% of participants achieving HbA1c ≤ 6.5% with tirzepatide 15 mg (Table 2, Figure 3).”
A reduction of 20-30% of basal insulin dose at the time of tirzepatide initiation has taken place in SURPASS trials to reduce the risk of hypoglycemia.
“A reduction of 20–30% of basal insulin dose at the time of tirzepatide initiation has taken place in SURPASS trials to reduce the risk of hypoglycemia [42,45].”
Up to 43% of people with T2D achieved ≥15% WL with tirzepatide 15 mg, even if tirzepatide was not combined with a lifestyle intervention at SURPASS programme.
“Mean WL ranged from −11.7 kg to −12.9 kg with tirzepatide 15 mg at 52 weeks and up to 43% of people with T2D achieved ≥ 15% WL, even if tirzepatide was not combined with a lifestyle intervention at SURPASS programme.”
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- Authors
- Rosenstock, J., Frías, J. P., Rodbard, H. W., Tofé, S., Sears, E., Huh, R., Fernández Landó, L., & Patel, H.
- Affiliations
- Medical City Dallas Hospital (US)
- Velocity Clinical Research (United States) (US)
- Endocrine and Metabolic Consultants, Rockville, Maryland
- Hospital Universitario Son Espases (ES)
- Eli Lilly (United States) (US)
- Eli Lilly and Company, Indianapolis, Indiana
- Corresponding author
- Rosenstock, Julio
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2023-11-07
- Volume
- 330
- Issue
- 17
- Pages
- 1631
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC10548360
- OpenAlex
- W4387296976
- Cited by
- 156
- References
- 15
- Citations by year
- 2026: 44 · 2025: 58 · 2024: 51 · 2023: 3
- FWCI
- 31.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- tirzepatide, insulin lispro, type 2 diabetes, basal insulin, insulin glargine, adjunctive therapy, glycemic control, HbA1c, non-inferiority, body weight, GLP-1 receptor agonists, GIP receptor agonist, insulin dose reduction, hypoglycemia, adverse events, drug safety
- MeSH terms
- Insulin Glargine, Tirzepatide, Aged, Blood Glucose, Body Weight, Diabetes Mellitus, Type 2, Female, Glycated Hemoglobin, Humans, Hypoglycemia, Hypoglycemic Agents, Insulin, Male, Middle Aged, Treatment Outcome, Internationality, Insulin Lispro
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