Full text is available at the source.
Lancet (London, England)···
Tirzepatide compared to insulin glargine in type 2 diabetes patients with higher heart risk
Updated
Abstract
At 52 weeks, mean HbA1c reductions were -2.43% for tirzepatide 10 mg and -2.58% for tirzepatide 15 mg, compared to -1.44% for insulin glargine.
- Tirzepatide met the non-inferiority margin for HbA1c change compared to glargine.
- Patients on tirzepatide experienced more gastrointestinal side effects, with nausea occurring in 12-23% and diarrhea in 13-22%.
- The incidence of hypoglycemia was lower with tirzepatide (6-9%) than with glargine (19%), especially among those not using sulfonylureas.
- Major adverse cardiovascular events occurred in 109 participants, with no significant increase in risk associated with tirzepatide compared to glargine.
- The overall mortality rate was similar between tirzepatide (3%) and glargine (4%) groups.
Simplified
BACKGROUND: We aimed to assess efficacy and safety, with a special focus on cardiovascular safety, of the novel dual GIP and GLP-1 receptor agonist tirzepatide versus insulin glargine in adults with type 2 diabetes and high cardiovascular risk inadequately controlled on oral glucose-lowering medications.
METHODS: This open-label, parallel-group, phase 3 study was done in 187 sites in 14 countries on five continents. Eligible participants, aged 18 years or older, had type 2 diabetes treated with any combination of metformin, sulfonylurea, or sodium-glucose co-transporter-2 inhibitor, a baseline glycated haemoglobin (HbA) of 7·5-10·5% (58-91 mmol/mol), body-mass index of 25 kg/mor greater, and established cardiovascular disease or a high risk of cardiovascular events. Participants were randomly assigned (1:1:1:3) via an interactive web-response system to subcutaneous injection of either once-per-week tirzepatide (5 mg, 10 mg, or 15 mg) or glargine (100 U/mL), titrated to reach fasting blood glucose of less than 100 mg/dL. The primary endpoint was non-inferiority (0·3% non-inferiority boundary) of tirzepatide 10 mg or 15 mg, or both, versus glargine in HbAchange from baseline to 52 weeks. All participants were treated for at least 52 weeks, with treatment continued for a maximum of 104 weeks or until study completion to collect and adjudicate major adverse cardiovascular events (MACE). Safety measures were assessed over the full study period. This study was registered with ClinicalTrials.gov, NCT03730662. 1c1c2
FINDINGS: Patients were recruited between Nov 20, 2018, and Dec 30, 2019. 3045 participants were screened, with 2002 participants randomly assigned to tirzepatide or glargine. 1995 received at least one dose of tirzepatide 5 mg (n=329, 17%), 10 mg (n=328, 16%), or 15 mg (n=338, 17%), or glargine (n=1000, 50%), and were included in the modified intention-to-treat population. At 52 weeks, mean HbAchanges with tirzepatide were -2·43% (SD 0·05) with 10 mg and -2·58% (0·05) with 15 mg, versus -1·44% (0·03) with glargine. The estimated treatment difference versus glargine was -0·99% (multiplicity adjusted 97·5% CI -1·13 to -0·86) for tirzepatide 10 mg and -1·14% (-1·28 to -1·00) for 15 mg, and the non-inferiority margin of 0·3% was met for both doses. Nausea (12-23%), diarrhoea (13-22%), decreased appetite (9-11%), and vomiting (5-9%) were more frequent with tirzepatide than glargine (nausea 2%, diarrhoea 4%, decreased appetite <1%, and vomiting 2%, respectively); most cases were mild to moderate and occurred during the dose-escalation phase. The percentage of participants with hypoglycaemia (glucose <54 mg/dL or severe) was lower with tirzepatide (6-9%) versus glargine (19%), particularly in participants not on sulfonylureas (tirzepatide 1-3% vs glargine 16%). Adjudicated MACE-4 events (cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina) occurred in 109 participants and were not increased on tirzepatide compared with glargine (hazard ratio 0·74, 95% CI 0·51-1·08). 60 deaths (n=25 [3%] tirzepatide; n=35 [4%] glargine) occurred during the study. 1c
INTERPRETATION: In people with type 2 diabetes and elevated cardiovascular risk, tirzepatide, compared with glargine, demonstrated greater and clinically meaningful HbAreduction with a lower incidence of hypoglycaemia at week 52. Tirzepatide treatment was not associated with excess cardiovascular risk. 1c
FUNDING: Eli Lilly and Company.
Related papers
Aug '21
Weekly tirzepatide compared to daily insulin as add-on treatments for type 2 diabetes with metformin, with or without SGLT2 inhibitors
top 1% journal
cited by 536 papers
randomized controlled trial
Sep '22
Tirzepatide compared to insulin glargine and their effects on kidney health in type 2 diabetes
top 1% journal
cited by 242 papers
randomized controlled trial
Jun '21
Effectiveness and safety of tirzepatide, a new drug activating two blood sugar control systems, in people with type 2 diabetes
top 1% journal
cited by 876 papers
randomized controlled trial
Mar '17
Effectiveness and safety of weekly semaglutide compared to daily insulin glargine added to metformin in people with type 2 diabetes who have not used insulin
top 1% journal
cited by 393 papers
randomized controlled trial
Apr '22
Weekly tirzepatide compared to daily insulin degludec for blood sugar control in adults with type 2 diabetes measured by continuous glucose monitoring
top 1% journal
cited by 51 papers
randomized controlled trial
Feb '22
Tirzepatide injection added to adjusted insulin improves blood sugar control in type 2 diabetes compared to placebo
top 1% journal
cited by 528 papers
randomized controlled trial
Apr '22
Tirzepatide versus insulin degludec effects on liver fat and belly fat in people with type 2 diabetes
top 1% journal
cited by 417 papers
randomized controlled trial
Jun '18
Dulaglutide compared to insulin glargine in type 2 diabetes patients with moderate-to-severe kidney disease
top 1% journal
cited by 560 papers
randomized controlled trial
Oct '18
Safety and effectiveness of LY3298176, a new drug targeting two hormone receptors, in people with type 2 diabetes: a controlled phase 2 trial
top 1% journal
cited by 714 papers
randomized controlled trial
Apr '22
Tirzepatide compared to placebo or semaglutide on insulin production and sensitivity in adults with type 2 diabetes
top 1% journal
cited by 219 papers
randomized controlled trial