Why This Is Important
People with diabetes mellitus (DM) type 2 often require long-acting and short-acting insulin to reach a treatment goal of hemoglobin A1c (HgbA1c) of less than 7.0%. However, adherence to these regimens is difficult and hypoglycemia and weight gain are common side effects.1
A previous study demonstrated that tirzepatide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) and gastric inhibitory polypeptide (GIP) receptor agonist, was superior to long-acting insulin for Hgb A1c reduction.2
This randomized controlled trial evaluated the effectiveness of tirzepatide to reduce hemoglobin A1c compared with mealtime insulin (insulin lispro) for people with type 2 DM taking basal insulin.3
Results
1,428 patients were randomized in the study.
The average baseline Hgb A1c was 8.8%, average age was 59 years old, 58% of patients were women, 62% were Hispanic, and 4% were Black.
For patients randomized to tirzepatide, the pooled average Hgb A1c was reduced by 2.1% (to 6.69%) compared with a reduction of HbgA1c of 1.13% (to 7.67%) for patients randomized to insulin lispro, an absolute difference of -0.98% between groups (95% CI -1.17 to -0.79%, p < 0.001) (Fig. 1).
HbA1c decreased proportionately with higher doses of tirzepatide; HbA1c reduction was 1.9%, 2.2%, and 2.3% with tirzepatide 5 mg, 10 mg, and 15 mg, respectively.
The reduction in A1c was found to be non-inferior to insulin lispro.
Weight decreased an average of -9.0 kg (19.8 lb) for patients randomized to tirzepatide and increased an average of 3.2 kg (7.1 lb) for those randomized to insulin lispro, for a total difference of 12.2 kg (26.9 lb) (95% CI -13.4 to -10.9).
Hypoglycemic events (ie, blood glucose (BG) < 54 mg/dL) occurred in 10.6% of patients randomized to tirzepatide and 48.0% of patients randomized to insulin lispro.
Nausea, decreased appetite, and diarrhea occurred in 19.9%, 12.3%, and 12.7% of patients taking tirzepatide, respectively, compared to 1.1%, 0.1%, and 2.4% for those taking insulin lispro.
Figure 1.
Comparison of Hgb A1c and weight change at 52 weeks.
Study Description
Setting
This study included patients 18 years or older with DM type 2 whose Hgb A1c was 7.5-11.0% despite treatment with a long-acting insulin. During a 10-week stabilization period all patients were placed on a standardized, long-acting insulin (glargine) regimen. Glucose lowering medications besides metformin were stopped.
Exclusion Criteria
Patients were excluded if they had DM type 1, were already on a GLP1-RA or a SGLT2 inhibitor, or had a contraindication to using a GLP-RA such as pancreatitis, diabetes-associated retinopathy, or severe kidney dysfunction (eGFR less than 30 mL/min/1.73 m2).
Intervention
Patients were randomized in a 1:1:1:3 ratio to tirzepatide 5 mg, 10 mg, and 15 mg, versus mealtime lispro, respectively.
Long-acting insulin doses were adjusted to reach a goal fasting BG 100–125 mg/dL. The median dose of insulin glargine was 46 units at the start of the study and 84.3% were taking metformin.
Tirzepatide doses were not adjusted to a specific BG. Insulin lispro doses were adjusted to goal pre-lunch, pre-dinner, and bedtime BG levels 100–125 mg/dL.
Outcomes (Hgb A1c, weight change, and hypoglycemic events) were assessed at week 52 of treatment.
Study Quality and Application for Patients
The quality of this study is good.
Its strengths include the randomization and stratified enrollment of patients, and low dropout rate (2.6%).
The study assessed multiple outcomes important to patients included Hgb A1c, weight loss, and hypoglycemia events.
Concerns include a discontinuation rate up to 8.9% for patients taking tirzepatide due to an adverse event.
Patients randomized to mealtime insulin had higher than expected median glucose levels compared with patients treated with tirzepatide. The reason for this could be increased hypoglycemic events in patients treated with mealtime insulin, which limited further increases in insulin doses.
Declarations:
Conflict of Interest:
None for any of the study authors.
Footnotes
Tip for patients: For patients with type 2 diabetes mellitus already on long-acting insulin, tirzepatide was no worse than mealtime insulin for reducing Hgb A1c but with fewer injections, fewer hypoglycemia events, and more weight loss.
Rosenstock J, Frías JP, Rodbard HW, et al. Tirzepatide vs Insulin Lispro Added to Basal Insulin in Type 2 Diabetes: The SURPASS-6 Randomized Clinical Trial. JAMA. 2023;330(17):1631–1640. doi:10.1001/jama.2023.20294.
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References
- 1.ElSayed NA, Aleppo G, Aroda VR, et al., on behalf of the American Diabetes Association. 6. Glycemic Targets: Standards of Care in Diabetes-2023. Diabetes Care. 2023 Jan 1;46(Suppl 1):S97-S110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Ludvik B, Giorgino F, Jódar E, 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 Aug 14;398(10300):583-598. doi: 10.1016/S0140-6736(21)01443-4. Epub 2021 Aug 6. PMID: 34370970. [DOI] [PubMed] [Google Scholar]
- 3.Rosenstock J, Frías JP, Rodbard HW, et al. Tirzepatide vs Insulin Lispro Added to Basal Insulin in Type 2 Diabetes: The SURPASS-6 Randomized Clinical Trial. JAMA. 2023;330(17):1631–1640. doi:10.1001/jama.2023.20294. [DOI] [PMC free article] [PubMed] [Google Scholar]