BACKGROUND: Tirzepatide is a novel dual glucose-dependent insulinotropic 
polypeptide and GLP-1 receptor agonist under development for the treatment of 
type 2 diabetes. We aimed to assess the efficacy and safety of tirzepatide 
versus titrated insulin degludec in people with type 2 diabetes inadequately 
controlled by metformin with or without SGLT2 inhibitors.
METHODS: In this open-label, parallel-group, multicentre (122 sites), 
multinational (13 countries), phase 3 study, eligible participants (aged ≥18 
years) had a baseline glycated haemoglobin (HbA1c) of 7·0-10·5%, body-mass index 
of at least 25 kg/m2, stable weight, and were insulin-naive and treated with 
metformin alone or in combination with an SGLT2 inhibitor for at least 3 months 
before screening. Participants were randomly assigned (1:1:1:1), using an 
interactive web-response system, to once-weekly subcutaneous injection of 
tirzepatide (5, 10, or 15 mg) or once-daily subcutaneous injection of titrated 
insulin degludec, and were stratified by country, HbA1c, and concomitant use of 
oral antihyperglycaemic medications. Tirzepatide was initially given at 2·5 mg 
and the dose was escalated by 2·5 mg every 4 weeks until the assigned dose was 
reached. Insulin degludec was initially given at 10 U per day and was titrated 
once weekly to a fasting self-monitored blood glucose of less than 5·0 mmol/L 
(<90 mg/dL), following a treat-to-target algorithm, for 52 weeks. The primary 
efficacy endpoint was non-inferiority of tirzepatide 10 mg or 15 mg, or both, 
versus insulin degludec in mean change from baseline in HbA1c at week 52. Key 
secondary efficacy endpoints were non-inferiority of tirzepatide 5 mg versus 
insulin degludec in mean change from baseline in HbA1c at week 52, superiority 
of all doses of tirzepatide versus insulin degludec in mean change from baseline 
in HbA1c and bodyweight, and the proportion of participants achieving HbA1c of 
less than 7·0% (<53 mmol/mol) at week 52. We used a boundary of 0·3% to 
establish non-inferiority in HbA1c difference between treatments. Efficacy and 
safety analyses were assessed in the modified intention-to-treat population (all 
participants who received at least one dose of study drug). This trial is 
registered with ClinicalTrials.gov, number NCT03882970, and is complete.
FINDINGS: Between April 1 and Nov 15, 2019, we assessed 1947 participants for 
eligibility, 1444 of whom were randomly assigned to treatment. The modified 
intention-to-treat population was 1437 participants from the tirzepatide 5 mg 
(n=358), tirzepatide 10 mg (n=360), tirzepatide 15 mg (n=359), and insulin 
degludec (n=360) groups. From a mean baseline HbA1c of 8·17% (SD 0·91), the 
reductions in HbA1c at week 52 were 1·93% (SE 0·05) for tirzepatide 5 mg, 2·20% 
(0·05) for tirzepatide 10 mg, and 2·37% (0·05) for tirzepatide 15 mg, and 1·34% 
(0·05) for insulin degludec. The non-inferiority margin of 0·3% was met. The 
estimated treatment difference (ETD) versus insulin degludec ranged from -0·59% 
to -1·04% for tirzepatide (p<0·0001 for all tirzepatide doses). The proportion 
of participants achieving a HbA1c of less than 7·0% (<53 mmol/mol) at week 52 
was greater (p<0·0001) in all three tirzepatide groups (82%-93%) versus insulin 
degludec (61%). At week 52, from a baseline of 94·3 kg (SD 20·1), all three 
tirzepatide doses decreased bodyweight (-7·5 kg to -12·9 kg), whereas insulin 
degludec increased bodyweight by 2·3 kg. The ETD versus insulin degludec ranged 
from -9·8 kg to -15·2 kg for tirzepatide (p<0·0001 for all tirzepatide doses). 
The most common adverse events in tirzepatide-treated participants were mild to 
moderate gastrointestinal events that decreased over time. A higher incidence of 
nausea (12-24%), diarrhoea (15-17%), decreased appetite (6-12%), and vomiting 
(6-10%) was reported in participants treated with tirzepatide than in those 
treated with insulin degludec (2%, 4%, 1%, and 1%, respectively). Hypoglycaemia 
(<54 mg/dL or severe) was reported in five (1%), four (1%), and eight (2%) 
participants on tirzepatide 5, 10, and 15 mg, respectively, versus 26 (7%) on 
insulin degludec. Treatment discontinuation due to an adverse event was more 
common in the tirzepatide groups than in the insulin degludec group. Five 
participants died during the study; none of the deaths were considered by the 
investigators to be related to the study treatment.
INTERPRETATION: In patients with type 2 diabetes, tirzepatide (5, 10, and 15 mg) 
was superior to titrated insulin degludec, with greater reductions in HbA1c and 
bodyweight at week 52 and a lower risk of hypoglycaemia. Tirzepatide showed a 
similar safety profile to that of GLP-1 receptor agonists.
FUNDING: Eli Lilly and Company.