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Tirzepatide vs Insulin Lispro Added to Basal Insulin in Type 2 Diabetes
TAKE-HOME MESSAGE
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This randomized clinical trial compared the efficacy and safety of tirzepatide (5, 10, or 15 mg) with those of insulin lispro (three times a day) in addition to insulin glargine. The outcomes included noninferiority of tirzepatide based on an HbA1c drop of at least 0.3%. The estimated difference in HbA1c levels between the two groups was −0.98% (P < .001). This met the threshold for noninferiority. Patients in the tirzepatide group had greater odds of reaching an HbA1c level of less than 7.0% (OR, 4.2).
- Clinicians should consider using tirzepatide for type 2 diabetes in addition to insulin glargine to achieve optimal blood glucose control.
abstract
This abstract is available on the publisher's site.
Access this abstract nowIMPORTANCE
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 HbA1c 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 A1c (HbA1c) 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] HbA1c, 8.8% [1.0%]), 1304 (91.3%) completed the trial. At week 52, estimated mean change from baseline in HbA1c with tirzepatide (pooled cohort) was -2.1% vs -1.1% with insulin lispro, resulting in mean HbA1c 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 HbA1c 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 HbA1c and body weight with less hypoglycemia.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04537923.
Additional Info
Disclosure statements are available on the authors' profiles:
Tirzepatide vs Insulin Lispro Added to Basal Insulin in Type 2 Diabetes: The SURPASS-6 Randomized Clinical Trial
JAMA 2023 Oct 03;[EPub Ahead of Print], J Rosenstock, JP Frías, HW Rodbard, S Tofé, E Sears, R Huh, L Fernández Landó, H PatelFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Tirzepatide is a dual GIP/GLP-1 receptor agonist approved for type 2 diabetes management. In the 52-week phase IIIb SURPASS-6 trial, 1428 patients with inadequately controlled type 2 diabetes on basal insulin with or without oral medications were randomized to tirzepatide (5 mg [n = 243], 10 mg [n = 238], or 15 mg [n = 236]) or prandial thrice-daily insulin lispro (n = 708). The enrolled population adequately represented both genders (57.7% women) and was largely composed of obese individuals (mean BMI, 33 kg/m2) with uncontrolled (mean baseline HbA1c, 8.8%) longstanding diabetes (mean duration, 14 years). Treatment with tirzepatide (pooled cohort) induced a greater HbA1c reduction compared with insulin lispro, with a mean HbA1c at week 52 of 6.7% versus 7.7% (−2.1% vs −1.1%, respectively, vs baseline; estimated treatment difference, −0.98%; 95% CI, −1.17% to −0.79%; P < .001). Of note, all doses of tirzepatide were significantly superior to insulin lispro in HbA1c-lowering. In addition, tirzepatide exhibited an insulin-sparing effect; insulin glargine dose decreased more than 70% throughout the study in patients receiving tirzepatide, with up to 19% of them even undergoing complete discontinuation. As expected, tirzepatide was associated with a mean body weight (BW) loss of −9.0 kg as opposed to a +3.2 kg weight gain with insulin lispro (estimated treatment difference, −12.2 kg; 95% CI, −13.4 to −10.9; P < .01). Moreover, insulin lispro was associated with a significantly greater hypoglycemia event rate, defined as blood glucose <54 mg/dL or severe hypoglycemia, compared with tirzepatide (4.4 vs 0.4 events/patient-year).
In this trial, tirzepatide has been proven more effective than prandial insulin as add-on to basal insulin, surpassing what was conventionally considered the last resource to achieve glucose control (ie, basal-bolus insulin therapy) while also reducing body weight, insulin doses, and hypoglycemia risk and allowing treatment simplification in keeping with current guidelines. However, the generalizability of these results in everyday clinical practice, with less stringent glucose targets for insulin titration and including patients with a wider BMI range than in this trial, should be assessed in further studies. Nevertheless, the results of SURPASS-6 live up to the expectations surrounding tirzepatide, with the anticipation of a multifaceted revolution of diabetes care, spanning from potential for hyperglycemia remission, particularly in people with less severe disease and shorter disease duration, to improved efficacy and safety of treatment in individuals with more longstanding disease unable to achieve glucose control on basal insulin and oral medications.