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Randomized controlled trial

SURPASS-3: tirzepatide (Mounjaro) vs insulin degludec

At 52 weeks, HbA1c fell by 1.93, 2.20 and 2.37 percentage points with tirzepatide 5, 10 and 15 mg, and by 1.34 points with insulin degludec; the difference versus degludec ranged from −0.59 to −1.04 points by dose, and all doses were superior.

Ludvik B et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. The Lancet, 2021. DOI: 10.1016/S0140-6736(21)01443-4

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Key facts

Drug
tirzepatide
Design
Randomized controlled trial
Participants
1,444
Duration
52 weeks
Funding
Eli Lilly
Registry
NCT03882970
Population
1,444 adults with type 2 diabetes not controlled on metformin, alone or with an SGLT2 inhibitor, who had never used insulin, with HbA1c of 7.0 to 10.5% and a BMI of 25 or more, at 122 sites in 13 countries, randomized to tirzepatide 5, 10 or 15 mg once weekly or to titrated once-daily insulin degludec; 1,437 were analyzed (358, 360, 359 and 360 per group), with a mean starting HbA1c of 8.17% and mean weight of 94.3 kg.
Primary outcome
Non-inferiority of tirzepatide 10 mg, 15 mg or both versus insulin degludec in the change in HbA1c at 52 weeks, with a margin of 0.3 percentage points; superiority of all doses in HbA1c and weight was a key secondary objective.

What it found

At 52 weeks, HbA1c fell by 1.93, 2.20 and 2.37 percentage points with tirzepatide 5, 10 and 15 mg, and by 1.34 points with insulin degludec; the difference versus degludec ranged from −0.59 to −1.04 points by dose, and all doses were superior. HbA1c below 7.0% was reached by 82 to 93% on tirzepatide, compared with 61% on degludec. Weight changed by −7.5 to −12.9 kg with tirzepatide and rose by 2.3 kg with degludec (difference of −9.8 to −15.2 kg). According to the trial registry, these figures exclude data after stopping the drug or starting rescue medication, so they estimate the effect in those who stayed on treatment. There was more nausea (12 to 24% versus 2%), diarrhea (15 to 17% versus 4%) and vomiting (6 to 10% versus 1%) with tirzepatide, and more hypoglycemia below 54 mg/dL or severe with degludec (7% versus 1 to 2%).

Limitations

Funded by Eli Lilly, the maker of tirzepatide. It was an open-label trial: participants and investigators knew which treatment each person received. It compared tirzepatide with insulin titrated to a fasting glucose below 5.0 mmol/L (90 mg/dL), not with another GLP-1 receptor agonist, and weight rose on insulin, which widens the difference in kilograms. It only included people taking metformin who had never used insulin, and it lasted 52 weeks. Stopping treatment because of adverse events was more common with tirzepatide than with degludec.

What it means for you

In type 2 diabetes treated with metformin, weekly tirzepatide (Mounjaro) lowered HbA1c more than insulin degludec (Tresiba) and reduced weight, while weight rose by an average of 2.3 kg on insulin over 52 weeks; there was also less hypoglycemia with tirzepatide. It was an open-label trial funded by the maker of tirzepatide. Which treatment fits your case is something to discuss with your doctor.

Further reading

Related trials

  • tirzepatide and semaglutide40 weeks

    SURPASS-2

    HbA1c fell by 2.01, 2.24 and 2.30 percentage points with tirzepatide 5, 10 and 15 mg, compared with 1.86 points with semaglutide 1 mg.

  • tirzepatide and dulaglutideEvent-driven

    SURPASS-CVOT

    Over a median follow-up of 4.0 years, a major cardiovascular event occurred in 12.2% of patients on tirzepatide and 13.1% on dulaglutide.

  • tirzepatide72 weeks

    SURMOUNT-2

    In people with type 2 diabetes and obesity, tirzepatide reduced weight by 12.8% with 10 mg and 14.7% with 15 mg at 72 weeks, compared with 3.2% on placebo.

  • tirzepatide88 weeks

    SURMOUNT-4 (post hoc analysis)

    After switching from tirzepatide to placebo, the more weight people regained between week 36 and week 88, the more their cardiometabolic parameters worsened: waist circumference increased by 0.8 cm in those who regained less than 25% of the weight lost and by 14.7 cm in those who regained 75% or more.

Sources

The original paper and the records consulted for this summary, with the date they were accessed.

  1. The Lancet.Ludvik B, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet. 2021;398(10300):583-598.accessed .
  2. National Library of Medicine (PubMed).PubMed record PMID 34370970 (abstract).accessed .
  3. ClinicalTrials.gov (National Library of Medicine).ClinicalTrials.gov record NCT03882970 (results: analysis population of the HbA1c and weight outcomes).accessed .