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10-14-2020 | Tirzepatide | At a glance | Article

Updated October 2021

A quick guide to the SURPASS and SURMOUNT trials

Phase 3 trials of tirzepatide in type 2 diabetes and obesity

Eleanor McDermid

medwireNews: Tirzepatide (formerly known as LY3298176) is a novel glucose-lowering medication that stimulates the receptors for both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP)-1.

Phase 2 findings published in The Lancet in 2018 were promising, with the medication showing dose-dependent effects on glucose levels and bodyweight. It outperformed dulaglutide 1.5 mg/day at the highest doses, albeit in a small group of study participants.

The phase 3 trials are testing the medication as monotherapy, as an add-on to other treatments, and against established glucose-lowering drugs in people with type 2 diabetes, as well as a weight-loss agent in people with diabetes and obesity.

All the trials are sponsored by tirzepatide’s manufacturer, Eli Lilly. We provide a round-up of them below and will update this page with the results as they are released.

And click here for a linked commentary, in which Medicine Matters editorial board member John Wilding outlines the potential advantages of dual GIP-GLP-1 agonists as a treatment approach for people with type 2 diabetes.

The SURPASS trials


Trial population: Drug-naïve people with type 2 diabetes

Comparator treatment: Placebo

NCT03954834; published

SURPASS-1 tested tirzepatide at doses of 5, 10, and 15 mg, administered as a weekly subcutaneous injection, in people with type 2 diabetes who had elevated glycated hemoglobin (HbA1c) levels despite diet and exercise interventions.

As reported in The Lancet, the placebo-adjusted HbA1c reductions during 40 weeks of treatment ranged from 1.91% to 2.11% (20.80–23.10 mmol/mol), depending on the tirzepatide dose, and weight reductions ranged from 6.3 to 8.8 kg.

Up to 92% of participants taking tirzepatide achieved HbA1c below 7.0% (53 mmol/mol), compared with 19% of those taking placebo, and up to 52% versus 1% achieved levels below 5.7% (39 mmol/mol).

Related news story: SURPASS-1: Tirzepatide has ‘potent’ glucose-lowering and weight loss efficacy


Trial population: People taking metformin monotherapy

Comparator treatment: Semaglutide

NCT03987919; published

In SURPASS-2, tirzepatide at the same three weekly doses (5, 10, and 15 mg) was tested against weekly injections of the GLP-1 receptor agonist semaglutide 1.0 mg.

The findings published in The New England Journal of Medicine revealed HbA1c  reductions of up to 2.30 percentage points during 40 weeks of tirzepatide treatment, which were significantly greater than the 1.86 percentage point reduction achieved with semaglutide. Tirzepatide also resulted in significantly greater weight reductions, of up to 5.5 kg more than seen with semaglutide.

Related news story: Tirzepatide has efficacy edge over semaglutide in SURPASS-2


Trial population: People taking metformin with/without an SGLT2 inhibitor

Comparator treatment: Insulin degludec

NCT03882970; completed

In this trial, the investigators  compared the efficacy of weekly tirzepatide (5, 10, and 15 mg) with daily insulin degludec in people with poorly controlled blood glucose despite stable treatment with metformin with or without an SGLT (sodium-glucose cotransporter)2 inhibitor.

They reported at the virtual ADA 81st Scientific Sessions that participants taking the highest tirzepatide dose achieved an average 2.37 percentage point reduction in HbA1c after 52 weeks of treatment, which was significantly more than the 1.34 percentage point reduction for those taking degludec.

The tirzepatide groups lost an average of 7.5, 10.7, and 12.9 kg, compared with an average 2.3 kg gain in the degludec group, and they were significantly less likely to experience hypoglycemia.

Related news story: SURPASS-3: Tirzepatide proves better option than degludec for type 2 diabetes


Trial population: People at increased cardiovascular risk taking metformin with/without a sulfonylurea or SGLT2 inhibitor

Comparator treatment: Insulin glargine

NCT03730662; published

As reported in The Lancet, all three tirzepatide doses resulted in significantly greater HbA1c reduction than insulin glargine, at 2.58% (28.2 mmol/mol) for the highest dose (15 mg/week), compared with 1.44% (15.7 mmol/mol). Tirzepatide treatment also resulted in significantly more weight loss and less hypoglycemia.

The trial enrolled people with increased cardiovascular risk, with 87% of participants having previous events. Over an extended follow-up of up to 104 weeks, major adverse cardiovascular event rates were similar for those taking tirzepatide and glargine, at 5% and 6%, respectively.

Related news story: Tirzepatide preferable to glargine when OADs fail in SURPASS-4


Trial population: People taking insulin glargine

Comparator treatment: Placebo

NCT04039503; completed

The SURPASS-5 trial tested tirzepatide (5, 10, and 15 mg) in people taking insulin glargine for type 2 diabetes, with or without metformin.

As reported at the virtual ADA 81st Scientific Sessions, 40 weeks of treatment with glargine plus the highest tirzepatide dose resulted in an average 2.59% reduction in HbA1c, which was significantly greater than the 0.93% reduction seen for glargine and placebo.

Also, the tirzepatide group lost an average of 10.9 kg and reduced their insulin dose, whereas the placebo group gained 1.7 kg, on average, and their insulin dose rose by 75%.

Related news story: SURPASS-5: Glycemic, weight benefits of tirzepatide in insulin-dependent type 2 diabetes


Trial population: People taking metformin with/without a sulfonylurea

Comparator treatment: Insulin glargine

NCT04093752; estimated study completion in March 2022

This trial is testing tirzepatide versus insulin glargine, over a 40-week period, in people taking metformin with or without a sulfonylurea of at least half the maximum dose.


Trial population: People with type 2 diabetes, confirmed atherosclerotic cardiovascular disease, and overweight

Comparator treatment: Dulaglutide

NCT04255433; estimated study completion in October 2024

For its cardiovascular outcomes trial, tirzepatide is up against dulaglutide 1.5 mg, which has a confirmed cardioprotective effect.

The investigators are assessing a three-point major adverse cardiovascular event endpoint (myocardial infarction, stroke, and cardiovascular death), over an estimated maximum of 54 months.

Trials for the Japanese market


Trial population: People who are drug-naïve or taking monotherapy (discontinued before baseline)

Comparator treatment: Dulaglutide

NCT03861052; estimated study completion in April 2021

This trial in Japanese people with type 2 diabetes is comparing weekly tirzepatide (5, 10, or 15 mg) against weekly dulaglutide 0.75 mg in people taking no other glucose-lowering medications during the trial.

Follow-up will last for 52 weeks and the primary endpoint is change in HbA1c.


Trial population: People taking antidiabetes medications other than incretin-based classes

Comparator treatment: None

NCT03861039; estimated study completion in March 2021

This safety study will monitor adverse events in Japanese people given tirzepatide (5, 10, or 15 mg) in addition to non-incretin-based antidiabetes medications over 52 weeks of treatment.

A trial of tirzepatide for obesity


Trial population: People with type 2 diabetes plus obesity or BMI 27 kg/m2 and related comorbidities

Comparator treatment: Placebo

NCT04184622; estimated study completion in May 2024

The SURMOUNT-1 trial is testing the ability of tirzepatide to produce weight loss in people with diabetes and obesity.

Participants will take tirzepatide at doses of 5, 10, or 15 mg, and the co-primary endpoints are the percent change in bodyweight and the proportion of people attaining at least a 5% reduction in their baseline bodyweight by week 72.

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2020 Springer Healthcare Ltd, part of the Springer Nature Group

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